Therapeutic agents useful for treating pain

ABSTRACT

A compound of formula  
                 
 
     (wherein A, R 1 , R 2 , R 6 , m and n are disclosed herein) or a pharmaceutically acceptable salt thereof (a “Piperazine Compound”); pharmaceutical compositions comprising a Piperazine Compound; and methods for treating pain, urinary incontinence (UI), an addictive disorder, Parkinson&#39;s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington&#39;s chorea, amyotrophic lateral sclerosis (ALS), dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia and depression in an animal comprising administering to an animal in need thereof an effective amount of a Piperazine Compound are disclosed.

[0001] This application claims the benefit of U.S. provisionalapplication No. 60/376,803, filed May 2, 2002, and U.S. provisionalapplication No. ______ (Pennie & Edmonds LLP docket no. 6750-210-888),filed Apr. 3, 2003, the disclosure of each provisional application beingincorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

[0002] The present invention relates to Piperazine Compounds,compositions comprising a Piperazine Compound and methods for treatingor preventing a condition such as pain, urinary incontinence (UI), anaddictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia ordepression comprising administering to the animal in an animal in needthereof an effective amount of a Piperazine Compound.

2. BACKGROUND OF THE INVENTION

[0003] Pain is the most common symptom for which patients seek medicaladvice and treatment. Pain can be acute or chronic. While acute pain isusually self-limited, chronic pain persists for 3 months or longer andcan lead to significant changes in a patient's personality, lifestyle,functional ability and overall quality of life (K. M. Foley, Pain, inCecil Textbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20thed. 1996)).

[0004] Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or cental nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at both Group I mGluRs (mGluR1 andmGluR5) (M. E. Fundytus, CNS Drugs 15:29-58 (2001)) and vaniloidreceptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology12:372-379 (2002)) to pain processing. Inhibiting mGluR1 or mGluR5reduces pain, as shown by in vivo treatment with antibodies selectivefor either mGluR1 or mGluR5, where neuropathic pain in rats wasattenuated (M. E. Fundytus et al., NeuroReport 9:731-735 (1998)). It hasalso been shown that antisense oligonucleotide knockdown of mGluR1alleviates both neuropathic and inflammatory pain (M. E. Fundytus etal., British Journal of Pharmacology 132:354-367 (2001); M. E. Fundytuset al., Pharmacology, Biochemsitry & Behavior 73:401-410 (2002)). Smallmolecule antagonists for mGluR5-attenuated pain in in vivo animal modelsare disclosed in, e.g., K. Walker et al., Neuropharmacology 40: 1-9(2000) and A. Dogrul et al., Neuroscience Letters 292:115-118 (2000)).

[0005] Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. Inaddition to the above-listed treatments, neuropathic pain, which can bedifficult to treat, has also been treated with anti-epileptics (e.g.gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), NMDAantagonists (e.g. ketamine, dextromethorphan), topical lidocaine (forpost-herpetic neuralgia), and tricyclic antidepressants (e.g.fluoxetine, sertraline and amitriptyline).

[0006] UI is uncontrollable urination, generally caused bybladder-detrusor-muscle instability. UI affects people of all ages andlevels of physical health, both in health care settings and in thecommunity at large. At present, UI afflicts 15-30% of elderly peopleliving at home, one-third of those living in acute-care settings, and atleast one-half of those living in long-term care institutions (R. M.Resnick, Lancet 346:94 (1995)). Persons having UI are predisposed toalso having urinary-tract infections, pressure ulcers, perineal rashesand urosepsis. Psychosocially, UI is associated with embarrassment,social stigmatization, depression and a risk of institutionalization(Herzo et al., Annu. Rev. Gerontol. Geriatr. 9:74 (1989)). Economically,the costs of UI are great; in the United States alone, health-care costsassociated with UI are over $15 billion per annum.

[0007] Physiologic bladder contraction results in large part fromacetylcholine-induced stimulation of post-ganglionic muscarinic-receptorsites on bladder smooth muscle. Treatments for UI include theadministration of drugs having bladder-relaxant properties, which helpto control bladder-detrusor-muscle overactivity. For example,anticholinergics such as propantheline bromide and glycopyrrolate, andcombinations of smooth-muscle relaxants such as a combination of racemicoxybutynin and dicyclomine or an anticholinergic, have been used totreat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995);Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J.63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)).These drugs are not effective, however, in all patients havinguninhibited bladder contractions. Administration of anticholinergicmedications represent the mainstay of this type of treatment.

[0008] None of the existing commercial drug treatments for UI, however,has achieved complete success in all classes of UI patients, nor hastreatment occurred without significant adverse side effects. Forexample, drowsiness, dry mouth, constipation, blurred vision, headaches,tachycardia, and cardiac arrhythmia, which are related to theanticholinergic activity of traditional anti-UI drugs, can occurfrequently and adversely affect patient compliance. Yet despite theprevalence of unwanted anticholinergic effects in many patients,anticholinergic drugs are currently prescribed for patients having UI.The Merck Manual ofMedical Information 631-634 (R. Berkow ed., 1997).

[0009] Many drugs can cause physical and/or psychological addiction. Themost well known types of these drugs include opiates, such as heroin,opium, and morphine; sympathomimetics, including cocaine andamphetamines; sedative-hypnotics, including alcohol, benzodiazepines andbarbiturates; and nicotine, which has effects similar to opioids andsympathomimetics. Drug addiction is characterized by a craving orcompulsion for taking the drug and an inability to limit its intake.Additionally, drug dependence is associated with drug tolerance, theloss of effect of the drug following repeated administration, andwithdrawal, the appearance of physical and behavioral symptoms when thedrug is not consumed. Sensitization occurs if repeated administration ofa drug leads to an increased response to each dose. Tolerance,sensitization, and withdrawal are phenomena evidencing a change in thecentral nervous system resulting from continued use of the drug. Thischange can motivate the addicted individual to continue consuming thedrug despite serious social, legal, physical and/or professionalconsequences. (See, e.g., U.S. Pat. No. 6,109,269 to Rise et al.).

[0010] Certain pharmaceutical agents have been administered for treatingaddiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use ofnontoxic NMDA-blocking agents co-administered with an addictivesubstance to prevent the development of tolerance or withdrawalsymptoms. U.S. Pat. No. 5,574,052 to Rose et al. disclosesco-administration of an addictive substance with an antagonist topartially block the pharmacological effects of the substance. U.S. Pat.No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiateagonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No.5,232,934 to Downs discloses administration of 3-phenoxypyridine totreat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato etal. disclose using a serotonin antagonist to treat chemical addiction.U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF orNT-4 growth factors to inhibit or reverse neurological adaptive changesthat correlate with behavioral changes in an addicted individual. U.S.Patent. No. 5,762,925 to Sagan discloses implanting encapsulated adrenalmedullary cells into an animal's central nervous system to inhibit thedevelopment of opioid intolerance. U.S. Pat. No. 6,204,284 to Beer etal. discloses racemic(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in theprevention or relief of a withdrawal syndrome resulting from addictionto drugs and for the treatment of chemical dependencies. Glutamaterelease is enhanced during opioid withdrawal (K. Jhamandas et al.,Journal of Neurosience 16:2758-2766 (1996)). Recent evidence suggests arole for Group I mGluRs in opioid tolerance and dependence. Aninteraction between opioids and mGluRs was demonstrated when it wasshown that an antagonist at Group I mGluRs significantly attenuatedwithdrawal symptoms in opioid-dependent rats (M. E. Fundytus et al.,British Journal of Pharmacology 113:1215-1220 (1994)). More recentresults show that antisense oligonucleotide knockdown of mGluR1 reducesprotein kinase C activity (M. E. Fundytus et al., British Journal ofPharmacology 132:354-367 (2001)), which may be associated in thedevelopment of opioid tolerance and dependence (see also M. E. Fundytus,CNS Drugs 15:29-58, (2001)). Very recently, it has been shown thatantisense oligonucleotide knockdown of mGluR1 attenuates the developmentof opioid tolerance (R. N. Sharif et al., British Journal ofPharmracology 136:865-872 (2002)). Selective antagonists of the mGluR5receptor have also been shown to exert anti-dependence activity in vivo(C. Chiamulera et al., Nature Neuroscience 4:873-874 (2001)).

[0011] Parkinson's disease is a clinical syndrome comprisingbradykinesia (slowness and poverty of movement), muscular rigidity,resting tremor (which usually abates during voluntary movement), and animpairment of postural balance leading to disturbance of gait andfalling. The features of Parkinson's disease are a loss of pigmented,dopaminergic neurons of the substantia nigra pars compacta and theappearance of intracellular inclusions known as Lewy bodies (Goodman andGillman's The Pharmaceutical Basis of Therapeutics 506 (9^(th) ed.1996)). Without treatment, Parkinson's disease progresses to a rigidakinetic state in which patients are incapable of caring for themselves.Death frequently results from complications of immobility, includingaspiration pneumonia or pulmonary embolism. Drugs commonly used for thetreatment of Parkinson's disease include carbidopa/levodopa, pergolide,bromocriptine, selegiline, amantadine, and trihexyphenidylhydrochloride. There remains, however, a need for drugs useful for thetreatment of Parkinson's disease and having an improved therapeuticprofile.

[0012] Anxiety is a fear, apprehension, or dread of impending dangeroften accompanied by restlessness, tension, tachycardia, and dyspnea.Other symptoms commonly associated with anxiety include depression,especially accompanied with dysthymic disorder (chronic “neurotic”depression); panic disorder; agoraphobia and other specific phobias;eating disorders; and many personality disorders. Often anxiety isunattached to a clearly identified treatable primary illness. If aprimary illness is found, however, it can be desirable to deal with theanxiety at the same time as the primary illness.

[0013] Currently, benzodiazepines are the most commonly usedanti-anxiety agents for generalized anxiety disorder. Benzodiazepines,however, carry the risk of producing impairment of cognition and skilledmotor functions, particularly in the elderly, which can result inconfusion, delerium, and falls with fractures. Sedatives are alsocommonly prescribed for treating anxiety. The azapirones, such asbuspirone, are also used to treat moderate anxiety. The azapirones,however, are less useful for treating severe anxiety accompanied withpanic attacks. Antagonists of the mGluR5 receptor have also been shownto exert anxiolytic and anti-depressant activity in in vivo animalmodels (E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430(2001) and P. J. M. Will et al., Trends in Pharmacological Sciences22(7):331-37 (2001)).

[0014] Epilepsy is a disorder characterized by the tendency to haverecurring seizures. The etiology commonly consists of lesions in somepart of the cortex, such as a tumor; developmental malformation; ordamage due to trauma or stroke. In some cases the etiology is genetic.An epileptic seizure can be triggered by repetitive sounds, flashinglights, video games, or touching certain parts of the body. Epilepsy istypically treated with anti-seizure drugs. In epilepsy cases, whereanti-seizure drugs are ineffective, and the defect in the brain isisolated to a small area of the brain, surgical removal of that part ofthe brain can be helpful in alleviating the seizures. In patients whohave several sources for the seizures or who have seizures that spreadquickly to all parts of the brain, surgical removal of the nerve fibersthat connect the two sides of the brain can be helpful.

[0015] A seizure is the result of abnormal electrical discharge in thebrain. The discharge can involve a small area of the brain and lead tothe person only noticing an odd taste or smell or it can involve a largearea of the brain and lead to convulsions, i.e., a seizure that causesjerking and spasms of the muscles throughout the body. Convulsions canalso result in brief attacks of altered consciousness and loss ofconsciousness, muscle control, or bladder control. A seizure is oftenpreceded by an aura, i.e., unusual sensation of smell, taste, or visionor an intense feeling that a seizure is about to begin. A seizuretypically lasts for about 2 to 5 minutes. When the seizure ends theperson can have headache, sore muscles, unusual sensations, confusion,and profound fatigue (postictal state). Usually the person cannotremember what happened during the seizure.

[0016] Examples of drugs for treating a seizure and epilepsy includecarbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital,phenytoin, primidone, valproic acid, trimethadione, benzodiazepines,γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however,can have side effects such as drowsiness; hyperactivity; hallucinations;inability to concentrate; central and peripheral nervous systemtoxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingivalhyperplasia; gastrointestinal disturbances such as nausea, vomiting,epigastric pain, and anorexia; endocrine effects such as inhibition ofantidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; andhypersensitivity such as scarlatiniform rash, morbilliform rash,Stevens-Johnson syndrome, systemic lupus erythematosus, and hepaticnecrosis; and hematological reactions such as red-cell aplasia,agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblasticanemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed.,1997).

[0017] A stroke or cerebrovascular accident, is the death of braintissue (cerebral infarction) resulting from the lack of blood flow andinsufficient oxygen to the brain. A stroke can be either ischemic orhemorrhagic. In an ischemic stroke, blood supply to the brain is cut offbecause of atherosclerosis or a blood clot that has blocked a bloodvessel. In a hemorrhagic stroke, a blood vessel bursts preventing normalblood flow and allowing blood to leak into an area of the brain anddestroying it. Most strokes develop rapidly and cause brain damagewithin minutes. In some cases, however, strokes can continue to worsenfor several hours or days. Symptoms of strokes vary depending on whatpart of the brain is effected. Symptoms include loss or abnormalsensations in an arm or leg or one side of the body, weakness orparalysis of an arm or leg or one side of the body, partial loss ofvison or hearing, double vision, dizziness, slurred speech, difficultyin thinking of the appropriate word or saying it, inability to recognizeparts of the body, unusual movements, loss of bladder control,imbalance, and falling, and fainting. The symptoms can be permanent andcan be associated with coma or stupor. Strokes can cause edema orswelling of the brain which can further damage brain tissue. For personssuffering from a stroke, intensive rehabilitation can help overcome thedisability caused by impairment of brain tissue. Rehabilitation trainsother parts of the brain to assume the tasks previously performed by thedamaged part.

[0018] Examples of drugs for treating strokes include anticoagulantssuch as heparin, drugs that break up clots such as streptokinase ortissue plasminogen activator, and drugs that reduce swelling such asmannitol or corticosteroids. The Merck Manual of Medical Information352-355 (R. Berkow ed., 1997).

[0019] Pruritus is an unpleasant sensation that prompts scratching.Pruritus can be attributed to dry skin, scabies, dermatitis,herpetiformis, atopic dermatitis, pruritus vulvae et ani, malaria,insect bites, pediculosis, contact dermatitis, drug reactions,urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus,lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullouspemphigoid, or fiberglass dermatitis. Conventionally, pruritus istreated by phototherapy with ultraviolet B or PUVA or with therapeuticagents such as naltrexone, nalmefene, danazol, and tricyclicantidepressants.

[0020] Selective antagonists of the metabotropic glutamate receptor 5(“mGluR5”) have been shown to exert analgesic activity in in vivo animalmodels (K. Walker et al., europharmacology 40:1-9 (2000) and A. Dogrulet al., Neuroscience Letters, 292(2):115-118 (2000)).

[0021] Selective antagonists of the mGluR5 receptor have also been shownto exert anti-Parkinson activity in vivo (K. J. Ossowska et al.,Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trendsin Pharmacological Sciences 22(7):331-37 (2001)).

[0022] Selective antagonists of the mGluR5 receptor have also been shownto exert anti-dependence activity in vivo (C. Chiamulera et al., NatureNeuroscience 4(9):873-74 (2001)).

[0023] International Publication No. WO 99/37304 by Rohne-Poulenc RorerPharmnaceuticals, Inc. discloses oxoazaheterocyclic compounds useful forinhibiting factor Xa.

[0024] There remains, however, a clear need in the art for new drugsuseful for treating or preventing pain, UI, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia ordepression.

[0025] Citation of any reference in Section 2 of this application is notto be construed as an admission that such reference is prior art to thepresent application.

3. SUMMARY OF THE INVENTION

[0026] The present invention encompasses compounds having the formula(I):

[0027] and pharmaceutically acceptable salts thereof, wherein:

[0028] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-, —CH(phenyl)- or —C(phenyl)₂—, each phenyl independently beingunsubstituted or substituted with one or more R₇ groups;

[0029] each R₁ is independently —H, —(C₁-C₃)alkyl, —O(C₁-C₃ alkyl),-halo, —OCF₃, —NO₂, —OH, —CN, —S(O)₂R₄, —C(O)OR₄, —OC(O)R₄, —NH₂ or—NHR₄;

[0030] R₂ is —(C₁—C₁₀)alkyl, —(C₂—C₁₀)alkenyl, -(C₂—C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0031] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups, or

[0032] R₂ is -(5- to 10-membered)heteroaryl, which is unsubstituted orsubstituted with one or more R₅′ groups;

[0033] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, ═NR₄,—CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR4,—S(O)R4 or —S(O)₂R₄;

[0034] each R₄ is independently —H, —(C₁—C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C8)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0035] each R₅ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂—C₆)alkenyl, —(C₂—C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄;

[0036] each R₅′ is independently —(C₁—C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂—C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0037] each R₆ is independently —(C₁—C₃ alkyl), —CH₂OH, —OH, -halo,—NO₂, —CN or —NH₂;

[0038] each R₇ is independently —(C₁—C₆)alkyl, —O(C₁—C₆)alkyl, halo,—C(halo)₃ or —OC(halo)₃;

[0039] m is 0, 1 or 2; and

[0040] n is an integer from 1-4.

[0041] The present invention also encompasses compounds having theformula (I), and pharmaceutically acceptable salts thereof, wherein:

[0042] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄alkyl)(C₁-C₄ alkyl)-, —CH(phenyl)- or —C(phenyl)₂—, each phenylindependently being unsubstituted or substituted with one or more R₇groups;

[0043] each R₁ is independently —H, —(C₁-C₃)alkyl, —O(C₁-C₃ alkyl),-halo, —OCF₃, —NO₂, —OH, —CN, —S(O)₂R₄, —C(O)OR₄, —OC(O)R₄, —NH2 or—NHR₄;

[0044] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0045] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0046] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, ═NR₄,—CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0047] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0048] each R₅ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄;

[0049] each R₆ is independently —(C₁-C₃ alkyl), —CH₂OH, —OH, -halo,—NO₂, —CN or —NH₂;

[0050] each R₇ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo,—C(halo)₃ or —OC(halo)₃;

[0051] m is 0, 1 or 2; and

[0052] n is an integer from 1-4.

[0053] The present invention also encompasses compounds having theformula (I), and pharmaceutically acceptable salts thereof, wherein:

[0054] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-;

[0055] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH, or —CN;

[0056] m is 0 or 1;

[0057] n is an integer from 1-4;

[0058] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0059] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups, or

[0060] R₂ is -(5- to 10-membered)heteroaryl which is unsubstituted orsubstituted with one or more R₅′ groups;

[0061] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0062] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0063] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄;

[0064] each R₅′ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄, or —S(O)₂R₄; and

[0065] each R₆ is —(C₁-C₃)alkyl.

[0066] The present invention also encompasses compounds having theformula (I), and pharmaceutically acceptable salts thereof, wherein:

[0067] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄alkyl)(C₁-C₄ alkyl)-;

[0068] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0069] m is 0 or 1;

[0070] n is an integer from 1-4;

[0071] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0072] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0073] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄, or —S(O)₂R₄;

[0074] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0075] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄; and

[0076] each R₆ is —(C₁-C₃)alkyl.

[0077] The present invention also encompasses compounds having theformula (Ia):

[0078] and pharmaceutically acceptable salts thereof, wherein:

[0079] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-;

[0080] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0081] n is an integer from 1-4;

[0082] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0083] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups, or

[0084] R₂ is -(5- to 10-membered)heteroaryl which is unsubstituted orsubstituted with one or more R₅′ groups;

[0085] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0086] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0087] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄; and

[0088] each R₅′ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄.

[0089] The present invention also encompasses compounds having theformula (Ia), and pharmaceutically acceptable salts thereof, wherein:

[0090] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄alkyl)(C₁-C₄ alkyl)-;

[0091] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0092] n is an integer from 1-4;

[0093] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0094] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0095] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0096] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂; and

[0097] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄.

[0098] A compound of formula (I), (Ia) or a pharmaceutically acceptablesalt thereof (a “Piperazine Compound”) is useful for treating orpreventing pain, UI, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia or depression (each beinga “Condition”) in an animal.

[0099] The invention also relates to compositions comprising aneffective amount of a Piperazine Compound and a pharmaceuticallyacceptable carrier or excipient. The compositions are useful fortreating or preventing a Condition.

[0100] The invention further relates to methods for treating aCondition, comprising administering to an animal in need thereof aneffective amount of a Piperazine Compound.

[0101] The invention further relates to methods for preventing aCondition, comprising administering to an animal in need thereof aneffective amount of a Piperazine Compound.

[0102] The invention still further relates to methods for inhibitingmGluR5 function in a cell, comprising contacting a cell capable ofexpressing mGluR5 with an effective amount of a Piperazine Compound.

[0103] The invention still further relates to methods for inhibitingmetabotropic glutamate receptor 1 (“mGluR1”) function in a cell,comprising contacting a cell capable of expressing mGluR1 with aneffective amount of a Piperazine Compound.

[0104] The invention still further relates to a method for preparing acomposition comprising the step of admixing a Piperazine Compound and apharmaceutically acceptable carrier or excipient.

[0105] The invention still further relates to a kit comprising acontainer containing an effective amount of a Piperazine Compound. Theinvention also relates to a kit comprising a container containing aneffective amount of a Piperazine Compound and instructions for using thePiperazine Compound to treat or prevent a Condition.

[0106] The present invention may be understood more fully by referenceto the following detailed description, figure and illustrative examples,which are intended to exemplify non-limiting embodiments of theinvention.

4. BRIEF DESCRIPTION OF THE DRAWINGS

[0107]FIG. 1 is a plot of calcium mobilization as measured by calciumfluoresence against log [Piperazine Compound AA] for the dose dependentinhibition of glutamate induced calcium mobilization in rat astrocytesin the presence of 10 μM glutamate.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Compounds of Formula (I)

[0108] The present invention encompasses compounds of Formula (I):

[0109] and pharmaceutically acceptable salts thereof, wherein:

[0110] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-, —CH(phenyl)- or —C(phenyl)₂—, each phenyl independently beingunsubstituted or substituted with one or more R₇ groups;

[0111] each R₁ is independently —H, —(C₁-C₃)alkyl, —O(C₁-C₃ alkyl),-halo, —CF₃, —OCF₃, —NO₂, —OH, —CN, —S(O)₂R₄, —C(O)OR₄, —OC(O)R₄, —NH₂,—NHR₄ or —N(R₄)₂;

[0112] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0113] R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered)heteroaryl, each of which is unsubstituted or substitutedwith one or more R₅ groups;

[0114] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, ═NR₄,—CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0115] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0116] each R₅ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄;

[0117] each R₆ is independently —(C₁-C₃ alkyl), —CH₂OH, —OH, -halo,—NO₂, —CN or —NH₂;

[0118] each R₇ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo,—C(halo)₃ or —OC(halo)₃;

[0119] m is 0, 1 or 2; and

[0120] n is an integer from 0-4.

[0121] In another embodiment, the present invention also encompassescompounds having the formula (I), and pharmaceutically acceptable saltsthereof, wherein:

[0122] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-, —CH(phenyl)- or —C(phenyl)₂—, each phenyl independently beingunsubstituted or substituted with one or more R₇ groups,

[0123] each R₁ is independently —H, —(C₁-C₃)alkyl, —O(C₁-C₃ alkyl),-halo, —OCF₃, —NO₂, —OH, —CN, —S(O)₂R₄, —C(O)OR₄, —OC(O)R₄, —NH₂ or—NHR₄;

[0124] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0125] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups, or

[0126] R₂ is -(5- to 10-membered)heteroaryl, which is unsubstituted orsubstituted with one or more R₅′ groups;

[0127] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, ═NR₄,—CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0128] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0129] each R₅ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄;

[0130] each R₅′ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0131] each R₆ is independently —(C₁-C₃ alkyl), —CH₂OH, —OH, -halo,—NO₂, —CN or —NH₂;

[0132] each R₇ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo,—C(halo)₃ or —OC(halo)₃;

[0133] m is 0, 1 or 2; and

[0134] n is an integer from 1-4.

[0135] The present invention also encompasses compounds having theformula (I), and pharmaceutically acceptable salts thereof, wherein:

[0136] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄alkyl)(C₁-C₄ alkyl)-, —CH(phenyl)- or —C(phenyl)₂—, each phenylindependently being unsubstituted or substituted with one or more R₇groups;

[0137] each R₁ is independently —H, —(C₁-C₃)alkyl, —O(C₁-C₃ alkyl),-halo, —CF₃, —OCF₃, —NO₂, —OH, —CN, —S(O)₂R₄, —C(O)OR₄, —OC(O)R₄, —NH₂,—NHR₄ or —N(R₄)₂;

[0138] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0139] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0140] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, ═NR₄,—CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0141] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0142] each R₅ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄;

[0143] each R₆ is independently —(C₁-C₃ alkyl), —CH₂OH, —OH, -halo,—NO₂, —CN or —NH₂;

[0144] each R₇ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo,—C(halo)₃ or —OC(halo)₃;

[0145] m is 0, 1 or 2; and

[0146] n is an integer from 0-4.

[0147] In another embodiment, the present invention also encompassescompounds having the formula (I), and pharmaceutically acceptable saltsthereof, wherein:

[0148] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄alkyl)(C₁-C₄ alkyl)-, —CH(phenyl)- or —C(phenyl)₂—, each phenylindependently being unsubstituted or substituted with one or more R₇groups;

[0149] each R₁ is independently —H, —(C₁-C₃)alkyl, —O(C₁-C₃ alkyl),-halo, —OCF₃, —NO₂, —OH, —CN, —S(O)₂R₄, —C(O)OR₄, —OC(O)R₄, —NH₂ or—NHR₄;

[0150] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0151] -phenyl, -naphthyl or —(C₁₄)aryl, each of which is unsubstitutedor substituted with one or more R₅ groups;

[0152] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, ═NR₄,—CH═NR₄, —NR₄₀H, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0153] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0154] each R₅ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄;

[0155] each R₆ is independently —(C₁-C₃ alkyl), —CH₂OH, —OH, -halo,—NO₂, —CN or —NH₂;

[0156] each R₇ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo,—C(halo)₃ or —OC(halo)₃;

[0157] m is 0, 1 or 2; and

[0158] n is an integer from 1-4.

[0159] The present invention also encompasses compounds having theformula (I), and pharmaceutically acceptable salts thereof, wherein:

[0160] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-;

[0161] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH, or —CN;

[0162] m is 0 or 1;

[0163] n is an integer from 1-4;

[0164] R₂ is —H, —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0165] R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered)heteroaryl, each of which is unsubstituted or substitutedwith one or more R₅ groups;

[0166] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0167] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0168] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄; and

[0169] each R₆ is —(C₁-C₃)alkyl.

[0170] In another embodiment, the present invention also encompassescompounds having the formula (I), and pharmaceutically acceptable saltsthereof, wherein:

[0171] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-;

[0172] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH, or —CN;

[0173] m is 0 or 1;

[0174] n is an integer from 1-4;

[0175] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0176] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups, or

[0177] R₂ is -(5- to 10-membered)heteroaryl which is unsubstituted orsubstituted with one or more R₅′ groups;

[0178] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0179] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0180] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄;

[0181] each R₅′ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄, or —S(O)₂R₄; and

[0182] each R₆ is —(C₁-C₃)alkyl.

[0183] In another embodiment A is —C(O)—.

[0184] In another embodiment, n is 1; R₁ is substituted at the3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN; andR₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each which is unsubstituted orsubstituted with one or more R₅ groups.

[0185] In another embodiment, n is 1; R₁ is substituted at the3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN; andR₂ is -(5- to 10-membered)heteroaryl, which is unsubstituted orsubstituted with one or more R₅′ groups.

[0186] In another embodiment, n is 1; R₁ is substituted at the3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN; andR₂ is —(C₁-C₁₀)alkyl, which is unsubstituted or substituted with one ormore R₃ groups.

[0187] In another embodiment A is —C(O)—; n is 1; R₁ is substituted atthe 3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH, or—CN; and R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered)heteroaryl, each which is unsubstituted or substituted withone or more R₅ groups.

[0188] In another embodiment A is —C(O)—; n is 1; R₁ is —NO₂ andsubstituted at the 3-position of the pyridyl ring; and R₂ is phenyl,which is unsubstituted or substituted with one or more R₅ groups.

[0189] In another embodiment A is —C(O)—, n is 1, R₁ is —NO₂ andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0190] In another embodiment A is —C(O)—, n is 1, R₁ is —CH₃, and R₂ isunsubstituted phenyl.

[0191] In another embodiment A is —C(O)—; n is 1; R₁ is —NO₂, -halo or—CN, each of which is substituted at the 3-position of the pyridyl ring;and R₂ is unsubstituted phenyl.

[0192] In another embodiment m is 0.

[0193] In another embodiment m is 1.

[0194] In another embodiment each R₆ is —CH₃.

[0195] The present invention also encompasses compounds having theformula (I), and pharmaceutically acceptable salts thereof, wherein:

[0196] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄alkyl)(C₁-C₄ alkyl)-;

[0197] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0198] m is 0 or 1;

[0199] n is an integer from 1-4;

[0200] R₂ is —H, —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0201] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0202] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄, or —S(O)₂R₄;

[0203] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0204] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄, or —S(O)₂R₄; and

[0205] each R₆ is —(C₁-C₃)alkyl.

[0206] In another embodiment, the present invention also encompassescompounds having the formula (I), and pharmaceutically acceptable saltsthereof, wherein:

[0207] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄alkyl)(C₁-C₄ alkyl)-;

[0208] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0209] m is 0 or 1;

[0210] n is an integer from 1-4;

[0211] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0212] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0213] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄, or —S(O)₂R₄;

[0214] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0215] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkeijyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄; and

[0216] each R₆ is —(C₁-C₃)alkyl.

[0217] In another embodiment A is —CH₂—, n is 1, R₁ is —NO₂ andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0218] In another embodiment A is —CH₂—, n is 2, an R₁ group is an —NO₂substituted at the 3-position of the pyridyl ring and the other R₁ groupis a —OH substituted at the 6-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0219] In another embodiment A is —CH₂—, n is 1, R₁ is —CN andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0220] In another embodiment A is —CH₂—, n is 1, R₁ is —Cl andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0221] In another embodiment m is 0.

[0222] In another embodiment m is 1.

[0223] In another embodiment each R₆ is —CH₃.

[0224] In the Piperazine Compounds of Formula (I), each R₆ can be on anycarbon of the piperazine ring. In one embodiment, the PiperazineCompounds have only one R₆ group, and that R₆ group is attached to acarbon atom adjacent to the nitrogen atom attached to the pyridinylgroup. In another embodiment, the Piperazine Compound has only one R₆group, and that R₆ group is attached to a carbon atom adjacent to thenitrogen atom attached to the A group.

[0225] In another embodiment, two R₆ groups are on a single atom of thepiperazine ring. In another embodiment, an R₆ group is attached to acarbon atom adjacent to the nitrogen atom attached to the pyridinylgroup and another R₆ group is attached to a carbon atom adjacent to thenitrogen atom attached to the A group.

[0226] In another embodiment, the Piperazine Compound has two R₆ groups,each being attached to a different carbon atom adjacent to a nitrogenatom attached to the pyridinyl group. In another embodiment, thePiperazine Compound has two R₆ groups, each being attached to adifferent carbon atom adjacent to a nitrogen atom attached to the Agroup.

[0227] In one embodiment, wherein the Piperazine Compound has one or twoR₆ groups, the carbon atom to which an R₆ group is attached has the (R)configuration. In another embodiment, wherein the Piperazine Compoundhas one or two R₆ groups, the carbon atom to which the R₆ group isattached has the (S) configuration. In another embodiment, thePiperazine Compound has one or two R₆ groups, and at least one of thecarbon atoms to which an R₆ group is attached has the (R) configuration.In another embodiment, the Piperazine Compound has one or two R₆ groups,and at least one of the carbon atoms to which an R₆ group is attachedhas the (S) configuration.

[0228] In another embodiment, the Piperazine Compound has one or two R₆groups, an R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the pyridinyl group, and the carbon to which the R₆group is attached is in the (R) configuration. In another embodiment,the Piperazine Compound has one or two R₆ groups, an R₆ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridinyl group, the carbon to which the R₆ group is attached is in the(R) configuration, and R₆ is —(C₁-C₃)alkyl. In another embodiment, thePiperazine Compound has one or two R₆ groups, an R₆ group is attached toa carbon atom adjacent to a nitrogen attached to the pyridinyl group,the carbon to which the R₆ group is attached is in the (R)configuration, and R₆ is —CH₃. In another embodiment, the PiperazineCompound has one or two R₆ groups, an R₆ group is attached to a carbonatom adjacent to a nitrogen attached to the pyridinyl group, the carbonto which the R₆ group is attached is in the (R) configuration, and R₆ is—CH₂OH. In another embodiment, the Piperazine Compound has one or two R₆groups, an R₆ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridinyl group, the carbon to which the R₆ group isattached is in the (R) configuration, and R₆ is —CH₂CH₃.

[0229] In another embodiment, the Piperazine Compound has one or two R₆groups, an R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the A group, and the carbon to which the R₆ group isattached is in the (R) configuration. In another embodiment, thePiperazine Compound has one or two R₆ groups, an R₆ group is attached toa carbon atom adjacent to a nitrogen attached to the A group, the carbonto which the R₆ group is attached is in the (R) configuration, and R₆ is—(C₁-C₃)alkyl. In another embodiment, the Piperazine Compound has one ortwo R₆ groups, an R₆ group is attached to a carbon atom adjacent to anitrogen attached to the A group, the carbon to which the R₆ group isattached is in the (R) configuration, and R₆ is —CH₃. In anotherembodiment, the Piperazine Compound has one or two R₆ groups, an R₆group is attached to a carbon atom adjacent to a nitrogen attached tothe A group, the carbon to which the R₆ group is attached is in the (R)configuration, and R₆ is —CH₂OH. In another embodiment, the PiperazineCompound has one or two R₆ groups, an & group is attached to a carbonatom adjacent to a nitrogen attached to the A group, the carbon to whichthe R₆ group is attached is in the (R) configuration, and R₆ is —CH₂CH₃.

[0230] In another embodiment, the Piperazine Compound has one or two R₆groups, an R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the pyridinyl group, and the carbon to which the R₆group is attached is in the (S) configuration. In another embodiment,the Piperazine Compound has one or two R₆ groups, an R₆ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridinyl group, the carbon to which the R₆ group is attached is in the(S) configuration, and R₆ is —(C₁-C₃)alkyl. In another embodiment, thePiperazine Compound has one or two R₆ groups, an R₆ group is attached toa carbon atom adjacent to a nitrogen attached to the pyridinyl group,the carbon to which the R₆ group is attached is in the (S)configuration, and R₆ is —CH₃. In another embodiment, the PiperazineCompound has one or two R₆ groups, an R₆ group is attached to a carbonatom adjacent to a nitrogen attached to the pyridinyl group, the carbonto which the R₆ group is attached is in the (S) configuration, and R₆ is—CH₂OH. In another embodiment, the Piperazine Compound has one or two R₆groups, an R₆ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridinyl group, the carbon to which the R₆ group isattached is in the (S) configuration, and R₆ is —CH₂CH₃.

[0231] In another embodiment, the Piperazine Compound has one or two R₆groups, an R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the A group, and the carbon to which the R₆ group isattached is in the (S) configuration. In another embodiment, thePiperazine Compound has one or two R₆ groups, an R group is attached toa carbon atom adjacent to a nitrogen attached to the A group, the carbonto which the R₆ group is attached is in the (S) configuration, and R₆ is—(C₁-C₃)alkyl. In another embodiment, the Piperazine Compound has one ortwo R₆ groups, an R₆ group is attached to a carbon atom adjacent to anitrogen attached to the A group, the carbon to which the R₆ group isattached is in the (S) configuration, and R₆ is —CH₃. In anotherembodiment, the Piperazine Compound has one or two R₆ groups, an R₆group is attached to a carbon atom adjacent to a nitrogen attached tothe A group, the carbon to which the R₆ group is attached is in the (S)configuration, and R₆ is —CH₂OH. In another embodiment, the PiperazineCompound has one or two R₆ groups, an R₆ group is attached to a carbonatom adjacent to a nitrogen attached to the A group, the carbon to whichthe R₆ group is attached is in the (S) configuration, and R₆ is —CH₂CH₃.

[0232] In another embodiment, the Piperazine Compound has only one R₆group, the R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the pyridinyl group, and the carbon to which the R₆group is attached is in the (R) configuration. In another embodiment,the Piperazine Compound has only one R₆ group, the R₆ group is attachedto a carbon atom adjacent to a nitrogen attached to the pyridinyl group,the carbon to which the & group is attached is in the (R) configuration,and R₆ is —(C₁-C₃)alkyl. In another embodiment, the Piperazine Compoundhas only one R₆ group, the R₆ group is attached to a carbon atomadjacent to a nitrogen attached to the pyridinyl group, the carbon towhich the R₆ group is attached is in the (R) configuration, and R₆ is—CH₃. In another embodiment, the Piperazine Compound has only one R6group, the R₆ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridinyl group, the carbon to which the R₆ group isattached is in the (R) configuration, and R₆ is —CH₂OH. In anotherembodiment, the Piperazine Compound has only one R₆ group, the R₆ groupis attached to a carbon atom adjacent to a nitrogen attached to thepyridinyl group, the carbon to which the R₆ group is attached is in the(R) configuration, and R₆ is —CH₂CH₃.

[0233] In another embodiment, the Piperazine Compound has only one R₆group, the R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the A group, and the carbon to which the R₆ group isattached is in the (R) configuration. In another embodiment, thePiperazine Compound has only one R₆ group, the R₆ group is attached to acarbon atom adjacent to a nitrogen attached to the A group, the carbonto which the R₆ group is attached is in the (R) configuration, and R₆ is—(C₁-C₃)alkyl. In another embodiment, the Piperazine Compound has onlyone R₆ group, the R₆ group is attached to a carbon atom adjacent to anitrogen attached to the A group, the carbon to which the R₆ group isattached is in the (R) configuration, and R₆ is —CH₃. In anotherembodiment, the Piperazine Compound has only one R₆ group, the R₆ groupis attached to a carbon atom adjacent to a nitrogen attached to the Agroup, the carbon to which the R₆ group is attached is in the (R)configuration, and R₆ is —CH₂OH. In another embodiment, the PiperazineCompound has only one R₆ group, the R₆ group is attached to a carbonatom adjacent to a nitrogen attached to the A group, the carbon to whichthe R₆ group is attached is in the (R) configuration, and R₆ is —CH₂CH₃.

[0234] In another embodiment, the Piperazine Compound has only one R₆group, the R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the pyridinyl group, and the carbon to which the R₆group is attached is in the (S) configuration. In another embodiment,the Piperazine Compound has only one R₆ group, the R₆ group is attachedto a carbon atom adjacent to a nitrogen attached to the pyridinyl group,the carbon to which the R₆ group is attached is in the (S)configuration, and R₆ is —(C₁-C₃)alkyl. In another embodiment, thePiperazine Compound has only one R₆ group, the R₆ group is attached to acarbon atom adjacent to a nitrogen attached to the pyridinyl group, thecarbon to which the R₆ group is attached is in the (S) configuration,and R₆ is —CH₃. In another embodiment, the Piperazine Compound has onlyone R₆ group, the R₆ group is attached to a carbon atom adjacent to anitrogen attached to the pyridinyl group, the carbon to which the R₆group is attached is in the (S) configuration, and R₆ is —CH₂OH. Inanother embodiment, the Piperazine Compound has only one R₆ group, theR₆ group is attached to a carbon atom adjacent to a nitrogen attached tothe pyridinyl group, the carbon to which the R₆ group is attached is inthe (S) configuration, and R₆ is —CH₂CH₃.

[0235] In another embodiment, the Piperazine Compound has only one R,group, the R₆ group is attached to a carbon atom adjacent to a nitrogenatom attached to the A group, and the carbon to which the R₆ group isattached is in the (S) configuration. In another embodiment, thePiperazine Compound has only one R₆ group, the R₆ group is attached to acarbon atom adjacent to a nitrogen attached to the A group, the carbonto which the R₆ group is attached is in the (S) configuration, and R₆ is—(C₁-C₃)alkyl. In another embodiment, the Piperazine Compound has onlyone R₆ group, the R₆ group is attached to a carbon atom adjacent to anitrogen attached to the A group, the carbon to which the R₆ group isattached is in the (S) configuration, and R₆ is —CH₃. In anotherembodiment, the Piperazine Compound has only one R₆ group, the R₆ groupis attached to a carbon atom adjacent to a nitrogen attached to the Agroup, the carbon to which the R₆ group is attached is in the (S)configuration, and R₆ is —CH₂OH. In another embodiment, the PiperazineCompound has only one R₆ group, the R₆ group is attached to a carbonatom adjacent to a nitrogen attached to the A group, the carbon to whichthe R₆ group is attached is in the (R) configuration, and R₆ is —CH₂CH₃.

[0236] In another embodiment, the R₆ group is attached to a carbon atomadjacent to a nitrogen attached to the A group. In another embodiment,the R₆ group is attached to a carbon atom adjacent to a nitrogenattached to the A group and the R₆ group is a —CH₃. In anotherembodiment, the R₆ group is attached to a carbon atom adjacent to anitrogen attached to the A group and the R₆ group is a —CH₂CH₃. Inanother embodiment, the R₆ group is attached to a carbon atom adjacentto a nitrogen attached to the A group and the carbon to which the R₆group is attached is in the (R) configuration. In another embodiment,the R₆ group is attached to a carbon atom adjacent to a nitrogenattached to the A group, the carbon to which the R₆ group is attached isin the (R) configuration, and the R₆ group is a —CH₃. In anotherembodiment, the R₆ group is attached to a carbon atom adjacent to anitrogen attached to the A group, the carbon to which the R₆ group isattached is in the (R) configuration, and the R₆ group is a —CH₂CH₃.

[0237] In another embodiment A is —C(O)—; n is 2; an R₁ is substitutedat the 4-position of the pyridinyl ring (denoted hereinafter forconvenience as “R₁′″”) and is —CH₃, —OCH₃ or -halo; the other R₁ issubstituted at the 6-position of the pyridinyl ring (denoted hereinafterfor convenience as “R₁′″”) and is —H or —CH₃; R₂ is -phenyl or -pyridyl,each which is unsubstituted or substituted with one or more R₅ or R₅′groups, as described above, and R₆ is —H, —CH₃ or —CH₂OH and is attachedto a carbon atom adjacent to the nitrogen atom attached to the A group.

[0238] In another embodiment A is —C(O)—; n is 2; R₁′ is —CH₃, —OCH₃ or—Cl; R₁′″ is —H or —CH₃; R₂ is -phenyl or -pyridyl, each which isunsubstituted or substituted with one or more R₅ or R₅′ groups, asdescribed above; and R₆ is —H, —CH₃ or —CH₂OH and is attached to acarbon atom adjacent to the nitrogen atom attached to the A group.

[0239] In another embodiment A is —C(O)—; n is 2; R_(l)′ is —CH₃, —OCH₃or -halo; R₁′″ is —H or —CH₃; R₂ is -phenyl or -pyridyl, each which isunsubstituted or substituted with one or more R₅ or R₅′ groups, asdescribed above, selected from -halo and —CH₃; and R₆ is —H, —CH₃ or—CH₂OH and is attached to a carbon atom adjacent to the nitrogen atomattached to the A group.

[0240] In another embodiment A is —C(O)—; n is 2; R₁′ is —CH₃, —OCH₃ or—Cl; R₁′″ is —H or —CH₃; R₂ is -phenyl or -pyridyl, each which isunsubstituted or substituted with one or more R₅ or R₅′ groups, asdescribed above, selected from —F, —Cl and —CH₃; and R₆ is —H, —CH₃ or—CH₂OH and is attached to a carbon atom adjacent to the nitrogen atomattached to the A group.

[0241] In another embodiment A is —C(O)—; n is 2; R₁′ is —CH₃, —OCH₃ or—Cl; R₁′″ is —H or —CH₃; R₂ is -phenyl which is unsubstituted orsubstituted with one R₅ group that is para to the phenyl group's pointof attachment to the triple bond and is selected from —F and —OCH₃; andR₆ is —H, —CH₃ or —CH₂OH and is attached to a carbon atom adjacent tothe nitrogen atom attached to the A group.

[0242] In another embodiment A is —C(O)—; n is 2; R₁′ is —CH₃, —OCH₃ or—Cl; R₁′″ is —H or —CH₃; R₂ is -pyridyl which is attached at its2-position and is unsubstituted or substituted with one R₅′ group at the5-position of the -pyridyl group's point of attachment to the triplebond and is selected from —F, —Cl and —CH₃; and R₆ is —H, —CH₃ or —CH₂OHand is attached to a carbon atom adjacent to the nitrogen atom attachedto the A group.

[0243] In another embodiment A is —C(O)—; n is 2; R₁′ is —CH₃, —OCH₃ or—Cl; R₁′″ is —H or —CH₃; R₂ is -pyridyl which is attached at its3-position and is unsubstituted or substituted with one R₅′ group at the6-position of the -pyridyl group's point of attachment to the triplebond and is selected from —F, —Cl and —CH₃; and R₆ is —H, —CH₃ or —CH₂OHand is attached to a carbon atom adjacent to the nitrogen atom attachedto the A group.

5.2 Compounds of Formula (Ia)

[0244] The present invention also encompasses compounds of Formula (Ia):

[0245] and pharmaceutically acceptable salts thereof, wherein:

[0246] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-;

[0247] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0248] n is an integer from 1-4;

[0249] R₂ is —H, —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0250] R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered)heteroaryl, each of which is unsubstituted or substitutedwith one or more R₅ groups;

[0251] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0252] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂; and

[0253] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄.

[0254] In another embodiment, the present invention also encompassescompounds having the formula (Ia), and pharmaceutically acceptable saltsthereof, wherein:

[0255] A is —C(O)—, —C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄alkyl)-;

[0256] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0257] n is an integer from 1-4;

[0258] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle or -(7- to I0-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or

[0259] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups, or

[0260] R₂ is -(5- to 10-membered)heteroaryl which is unsubstituted orsubstituted with one or more R₅′ groups;

[0261] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0262] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂;

[0263] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄; and

[0264] each R₅′ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄.

[0265] In another embodiment A is —C(O)—.

[0266] In another embodiment A is —C(O)—; n is 1; R₁ is substituted atthe 3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH, or—CN; and R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered)heteroaryl, each which is unsubstituted or substituted withone or more R₅ groups.

[0267] In another embodiment A is —C(O)—; n is 1; R₁ is —NO₂ andsubstituted at the 3-position of the pyridyl ring; and R₂ is phenyl,which is unsubstituted or substituted with one or more R₅ groups.

[0268] In another embodiment A is —C(O)—, n is 1, R₁ is —NO₂ andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0269] In another embodiment A is —C(O)—, n is 1, R₁ is —CH₃, and R₂ isunsubstituted phenyl.

[0270] In another embodiment A is —C(O)—; n is 1; R₁ is —NO₂, -halo or—CN, each of which is substituted at the 3-position of the pyridyl ring;and R₂ is unsubstituted phenyl.

[0271] The present invention also encompasses compounds having theformula (Ia), and pharmaceutically acceptable salts thereof, wherein:

[0272] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄ alkyl)-;

[0273] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0274] n is an integer from 1-4;

[0275] R₂ is —H, —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0276] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0277] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0278] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂; and

[0279] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄.

[0280] In another embodiment, the present invention also encompassescompounds having the formula (Ia), and pharmaceutically acceptable saltsthereof, wherein:

[0281] A is —C(O)—, —C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄alkyl)(C₁-C₄ alkyl)(C₁-C₄ alkyl)-;

[0282] each R₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN;

[0283] n is an integer from 1-4;

[0284] R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C1 ₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or

[0285] R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which isunsubstituted or substituted with one or more R₅ groups;

[0286] each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄;

[0287] each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂; and

[0288] each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄.

[0289] In another embodiment A is —CH₂—, n is 1, R₁ is —NO₂ andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0290] In another embodiment A is —CH₂—, n is 2, R₁ is an —NO₂substituted at the 3-position of the pyridyl ring, R₁′″ is a —OH and R₂is unsubstituted phenyl.

[0291] In another embodiment A is —CH₂—, n is 1, R₁ is —CN andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0292] In another embodiment A is —CH₂—, n is 1, R₁ is —Cl andsubstituted at the 3-position of the pyridyl ring, and R₂ isunsubstituted phenyl.

[0293] Illustrative compounds of formulas (I) and (Ia) have thestructure:

[0294] and pharmaceutically acceptable salts thereof.

[0295] Other illustrative compounds of formulas (I) and (Ia) are listedbelow in Table 1: TABLE 1

[0296] and pharmaceutically acceptable salts thereof, where: Compound R₆R₁ R₁′ R₁′′ R₁′′′ Y Z 100 (IIa) —H —H —H —H —H —C(H)— —C(H)— 101 (IIa)—H —H —H —H —H —C(H)— —N— 102 (IIa) —H —H —H —H —H —N— —C(H)— 103 (IIa)—H —H —H —H —CH₃ —C(H)— —C(H)— 104 (IIa) —H —H —H —H —CH₃ —C(H)— —N— 105(IIa) —H —H —H —H —CH₃ —N— —C(H)— 106 (IIa) —H —H —H —H —OCH₃ —C(H)——C(H)— 107 (IIa) —H —H —H —H —OCH₃ —C(H)— —N— 108 (IIa) —H —H —H —H—OCH₃ —N— —C(H)— 109 (IIa) —H —H —H —H —OCF₃ —C(H)— —C(H)— 110 (IIa) —H—H —H —H —OCF₃ —C(H)— —N— 111 (IIa) —H —H —H —H —OCF₃ —N— —C(H)— 112(IIa) —H —H —H —H —F —C(H)— —C(H)— 113 (IIa) —H —H —H —H —F —C(H)— —N—114 (IIa) —H —H —H —H —F —N— —C(H)— 115 (IIa) —H —H —H —CH₃ —H —C(H)——C(H)— 116 (IIa) —H —H —H —CH₃ —H —C(H)— —N— 117 (IIa) —H —H —H —CH₃ —H—N— —C(H)— 118 (IIa) —H —H —H —CH₃ —CH₃ —C(H)— —C(H)— 119 (IIa) —H —H —H—CH₃ —CH₃ —C(H)— —N— 120 (IIa) —H —H —H —CH₃ —CH₃ —N— —C(H)— 121 (IIa)—H —H —H —CH₃ —OCH₃ —C(H)— —C(H)— 122 (IIa) —H —H —H —CH₃ —OCH₃ —C(H)——N— 123 (IIa) —H —H —H —CH₃ —OCH₃ —N— —C(H)— 124 (IIa) —H —H —H —CH₃—OCF₃ —C(H)— —C(H)— 125 (IIa) —H —H —H —CH₃ —OCF₃ —C(H)— —N— 126 (IIa)—H —H —H —CH₃ —OCF₃ —N— —C(H)— 127 (IIa) —H —H —H —CH₃ —F —C(H)— —C(H)—128 (IIa) —H —H —H —CH₃ —F —C(H)— —N— 129 (IIa) —H —H —H —CH₃ —F —N——C(H)— 130 (IIa) —H —H —H —OCH₃ —H —C(H)— —C(H)— 131 (IIa) —H —H —H—OCH₃ —H —C(H)— —N— 132 (IIa) —H —H —H —OCH₃ —H —N— —C(H)— 133 (IIa) —H—H —H —OCH₃ —CH₃ —C(H)— —C(H)— 134 (IIa) —H —H —H —OCH₃ —CH₃ —C(H)— —N—135 (IIa) —H —H —H —OCH₃ —CH₃ —N— —C(H)— 136 (IIa) —H —H —H —OCH₃ —OCH₃—C(H)— —C(H)— 137 (IIa) —H —H —H —OCH₃ —OCH₃ —C(H)— —N— 138 (IIa) —H —H—H —OCH₃ —OCH₃ —N— —C(H)— 139 (IIa) —H —H —H —OCH₃ —OCF₃ —C(H)— —C(H)—140 (IIa) —H —H —H —OCH₃ —OCF₃ —C(H)— —N— 141 (IIa) —H —H —H —OCH₃ —OCF₃—N— —C(H)— 142 (IIa) —H —H —H —OCH₃ —F —C(H)— —C(H)— 143 (IIa) —H —H —H—OCH₃ —F —C(H)— —N— 144 (IIa) —H —H —H —OCH₃ —F —N— —C(H)— 145 (IIa) —H—H —H —NO₂ —H —C(H)— —C(H)— 146 (IIa) —H —H —H —NO₂ —H —C(H)— —N— 147(IIa) —H —H —H —NO₂ —H —N— —C(H)— 148 (IIa) —H —H —H —NO₂ —CH₃ —C(H)——C(H)— 149 (IIa) —H —H —H —NO₂ —CH₃ —C(H)— —N— 150 (IIa) —H —H —H —NO₂—CH₃ —N— —C(H)— 151 (IIa) —H —H —H —NO₂ —OCH₃ —C(H)— —C(H)— 152 (IIa) —H—H —H —NO₂ —OCH₃ —C(H)— —N— 153 (IIa) —H —H —H —NO₂ —OCH₃ —N— —C(H)— 154(IIa) —H —H —H —NO₂ —OCF₃ —C(H)— —C(H)— 155 (IIa) —H —H —H —NO₂ —OCF₃—C(H)— —N— 156 (IIa) —H —H —H —NO₂ —OCF₃ —N— —C(H)— 157 (IIa) —H —H —H—NO₂ —F —C(H)— —C(H)— 158 (IIa) —H —H —H —NO₂ —F —C(H)— —N— 159 (IIa) —H—H —H —NO₂ —F —N— —C(H)— 160 (IIa) —H —H —CH₃ —H —H —C(H)— —C(H)— 161(IIa) —H —H —CH₃ —H —H —C(H)— —N— 162 (IIa) —H —H —CH₃ —H —H —N— —C(H)—163 (IIa) —H —H —CH₃ —H —CH₃ —C(H)— —C(H)— 164 (IIa) —H —H —CH₃ —H —CH₃—C(H)— —N— 165 (IIa) —H —H —CH₃ —H —CH₃ —N— —C(H)— 166 (IIa) —H —H —CH₃—H —OCH₃ —C(H)— —C(H)— 167 (IIa) —H —H —CH₃ —H —OCH₃ —C(H)— —N— 168(IIa) —H —H —CH₃ —H —OCH₃ —N— —C(H)— 169 (IIa) —H —H —CH₃ —H —OCF₃—C(H)— —C(H)— 170 (IIa) —H —H —CH₃ —H —OCF₃ —C(H)— —N— 171 (IIa) —H —H—CH₃ —H —OCF₃ —N— —C(H)— 172 (IIa) —H —H —CH₃ —H —F —C(H)— —C(H)— 173(IIa) —H —H —CH₃ —H —F —C(H)— —N— 174 (IIa) —H —H —CH₃ —H —F —N— —C(H)—175 (IIa) —H —H —CH₃ —CH₃ —H —C(H)— —C(H)— 176 (IIa) —H —H —CH₃ —CH₃ —H—C(H)— —N— 177 (IIa) —H —H —CH₃ —CH₃ —H —N— —C(H)— 178 (IIa) —H —H —CH₃—CH₃ —CH₃ —C(H)— —C(H)— 179 (IIa) —H —H —CH₃ —CH₃ —CH₃ —C(H)— —N— 180(IIa) —H —H —CH₃ —CH₃ —CH₃ —N— —C(H)— 181 (IIa) —H —H —CH₃ —CH₃ —OCH₃—C(H)— —C(H)— 182 (IIa) —H —H —CH₃ —CH₃ —OCH₃ —C(H)— —N— 183 (IIa) —H —H—CH₃ —CH₃ —OCH₃ —N— —C(H)— 184 (IIa) —H —H —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)—185 (IIa) —H —H —CH₃ —CH₃ —OCF₃ —C(H)— —N— 186 (IIa) —H —H —CH₃ —CH₃—OCF₃ —N— —C(H)— 187 (IIa) —H —H —CH₃ —CH₃ —F —C(H)— —C(H)— 188 (IIa) —H—H —CH₃ —CH₃ —F —C(H)— —N— 189 (IIa) —H —H —CH₃ —CH₃ —F —N— —C(H)— 190(IIa) —H —H —CH₃ —OCH₃ —H —C(H)— —C(H)— 191 (IIa) —H —H —CH₃ —OCH₃ —H—C(H)— —N— 192 (IIa) —H —H —CH₃ —OCH₃ —H —N— —C(H)— 193 (IIa) —H —H —CH₃—OCH₃ —CH₃ —C(H)— —C(H)— 194 (IIa) —H —H —CH₃ —OCH₃ —CH₃ —C(H)— —N— 195(IIa) —H —H —CH₃ —OCH₃ —CH₃ —N— —C(H)— 196 (IIa) —H —H —CH₃ —OCH₃ —OCH₃—C(H)— —C(H)— 197 (IIa) —H —H —CH₃ —OCH₃ —OCH₃ —C(H)— —N— 198 (IIa) —H—H —CH₃ —OCH₃ —OCH₃ —N— —C(H)— 199 (IIa) —H —H —CH₃ —OCH₃ —OCF₃ —C(H)——C(H)— 200 (IIa) —H —H —CH₃ —OCH₃ —OCF₃ —C(H)— —N— 201 (IIa) —H —H —CH₃—OCH₃ —OCF₃ —N— —C(H)— 202 (IIa) —H —H —CH₃ —OCH₃ —F —C(H)— —C(H)— 203(IIa) —H —H —CH₃ —OCH₃ —F —C(H)— —N— 204 (IIa) —H —H —CH₃ —OCH₃ —F —N——C(H)— 205 (IIa) —H —H —CH₃ —NO₂ —H —C(H)— —C(H)— 206 (IIa) —H —H —CH₃—NO₂ —H —C(H)— —N— 207 (IIa) —H —H —CH₃ —NO₂ —H —N— —C(H)— 208 (IIa) —H—H —CH₃ —NO₂ —CH₃ —C(H)— —C(H)— 209 (IIa) —H —H —CH₃ —NO₂ —CH₃ —C(H)——N— 210 (IIa) —H —H —CH₃ —NO₂ —CH₃ —N— —C(H)— 211 (IIa) —H —H —CH₃ —NO₂—OCH₃ —C(H)— —C(H)— 212 (IIa) —H —H —CH₃ —NO₂ —OCH₃ —C(H)— —N— 213 (IIa)—H —H —CH₃ —NO₂ —OCH₃ —N— —C(H)— 214 (IIa) —H —H —CH₃ —NO₂ —OCF₃ —C(H)——C(H)— 215 (IIa) —H —H —CH₃ —NO₂ —OCF₃ —C(H)— —N— 216 (IIa) —H —H —CH₃—NO₂ —OCF₃ —N— —C(H)— 217 (IIa) —H —H —CH₃ —NO₂ —F —C(H)— —C(H)— 218(IIa) —H —H —CH₃ —NO₂ —F —C(H)— —N— 219 (IIa) —H —H —CH₃ —NO₂ —F —N——C(H)— 220 (IIa) —H —H —OCH₃ —H —H —C(H)— —C(H)— 221 (IIa) —H —H —OCH₃—H —H —C(H)— —N— 222 (IIa) —H —H —OCH₃ —H —H —N— —C(H)— 223 (IIa) —H —H—OCH₃ —H —CH₃ —C(H)— —C(H)— 224 (IIa) —H —H —OCH₃ —H —CH₃ —C(H)— —N— 225(IIa) —H —H —OCH₃ —H —CH₃ —N— —C(H)— 226 (IIa) —H —H —OCH₃ —H —OCH₃—C(H)— —C(H)— 227 (IIa) —H —H —OCH₃ —H —OCH₃ —C(H)— —N— 228 (IIa) —H —H—OCH₃ —H —OCH₃ —N— —C(H)— 229 (IIa) —H —H —OCH₃ —H —OCF₃ —C(H)— —C(H)—230 (IIa) —H —H —OCH₃ —H —OCF₃ —C(H)— —N— 231 (IIa) —H —H —OCH₃ —H —OCF₃—N— —C(H)— 232 (IIa) —H —H —OCH₃ —H —F —C(H)— —C(H)— 233 (IIa) —H —H—OCH₃ —H —F —C(H)— —N— 234 (IIa) —H —H —OCH₃ —H —F —N— —C(H)— 235 (IIa)—H —H —OCH₃ —CH₃ —H —C(H)— —C(H)— 236 (IIa) —H —H —OCH₃ —CH₃ —H —C(H)——N— 237 (IIa) —H —H —OCH₃ —CH₃ —H —N— —C(H)— 238 (IIa) —H —H —OCH₃ —CH₃—CH₃ —C(H)— —C(H)— 239 (IIa) —H —H —OCH₃ —CH₃ —CH₃ —C(H)— —N— 240 (IIa)—H —H —OCH₃ —CH₃ —CH₃ —N— —C(H)— 241 (IIa) —H —H —OCH₃ —CH₃ —OCH₃ —C(H)——C(H)— 242 (IIa) —H —H —OCH₃ —CH₃ —OCH₃ —C(H)— —N— 243 (IIa) —H —H —OCH₃—CH₃ —OCH₃ —N— —C(H)— 244 (IIa) —H —H —OCH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 245(IIa) —H —H —OCH₃ —CH₃ —OCF₃ —C(H)— —N— 246 (IIa) —H —H —OCH₃ —CH₃ —OCF₃—N— —C(H)— 247 (IIa) —H —H —OCH₃ —CH₃ —F —C(H)— —C(H)— 248 (IIa) —H —H—OCH₃ —CH₃ —F —C(H)— —N— 249 (IIa) —H —H —OCH₃ —CH₃ —F —N— —C(H)— 250(IIa) —H —H —OCH₃ —OCH₃ —H —C(H)— —C(H)— 251 (IIa) —H —H —OCH₃ —OCH₃ —H—C(H)— —N— 252 (IIa) —H —H —OCH₃ —OCH₃ —H —N— —C(H)— 253 (IIa) —H —H—OCH₃ —OCH₃ —CH₃ —C(H)— —C(H)— 254 (IIa) —H —H —OCH₃ —OCH₃ —CH₃ —C(H)——N— 255 (IIa) —H —H —OCH₃ —OCH₃ —CH₃ —N— —C(H)— 256 (IIa) —H —H —OCH₃—OCH₃ —OCH₃ —C(H)— —C(H)— 257 (IIa) —H —H —OCH₃ —OCH₃ —OCH₃ —C(H)— —N—258 (IIa) —H —H —OCH₃ —OCH₃ —OCH₃ —N— —C(H)— 259 (IIa) —H —H —OCH₃ —OCH₃—OCF₃ —C(H)— —C(H)— 260 (IIa) —H —H —OCH₃ —OCH₃ —OCF₃ —C(H)— —N— 261(IIa) —H —H —OCH₃ —OCH₃ —OCF₃ —N— —C(H)— 262 (IIa) —H —H —OCH₃ —OCH₃ —F—C(H)— —C(H)— 263 (IIa) —H —H —OCH₃ —OCH₃ —F —C(H)— —N— 264 (IIa) —H —H—OCH₃ —OCH₃ —F —N— —C(H)— 265 (IIa) —H —H —OCH₃ —NO₂ —H —C(H)— —C(H)—266 (IIa) —H —H —OCH₃ —NO₂ —H —C(H)— —N— 267 (IIa) —H —H —OCH₃ —NO₂ —H—N— —C(H)— 268 (IIa) —H —H —OCH₃ —NO₂ —CH₃ —C(H)— —C(H)— 269 (IIa) —H —H—OCH₃ —NO₂ —CH₃ —C(H)— —N— 270 (IIa) —H —H —OCH₃ —NO₂ —CH₃ —N— —C(H)—271 (IIa) —H —H —OCH₃ —NO₂ —OCH₃ —C(H)— —C(H)— 272 (IIa) —H —H —OCH₃—NO₂ —OCH₃ —C(H)— —N— 273 (IIa) —H —H —OCH₃ —NO₂ —OCH₃ —N— —C(H)— 274(IIa) —H —H —OCH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 275 (IIa) —H —H —OCH₃ —NO₂—OCF₃ —C(H)— —N— 276 (IIa) —H —H —OCH₃ —NO₂ —OCF₃ —N— —C(H)— 277 (IIa)—H —H —OCH₃ —NO₂ —F —C(H)— —C(H)— 278 (IIa) —H —H —OCH₃ —NO₂ —F —C(H)——N— 279 (IIa) —H —H —OCH₃ —NO₂ —F —N— —C(H)— 280 (IIa) —H —NO₂ —H —H —H—C(H)— —C(H)— 281 (IIa) —H —NO₂ —H —H —H —C(H)— —N— 282 (IIa) —H —NO₂ —H—H —H —N— —C(H)— 283 (IIa) —H —NO₂ —H —H —CH₃ —C(H)— —C(H)— 284 (IIa) —H—NO₂ —H —H —CH₃ —C(H)— —N— 285 (IIa) —H —NO₂ —H —H —CH₃ —N— —C(H)— 286(IIa) —H —NO₂ —H —H —OCH₃ —C(H)— —C(H)— 287 (IIa) —H —NO₂ —H —H —OCH₃—C(H)— —N— 288 (IIa) —H —NO₂ —H —H —OCH₃ —N— —C(H)— 289 (IIa) —H —NO₂ —H—H —OCF₃ —C(H)— —C(H)— 290 (IIa) —H —NO₂ —H —H —OCF₃ —C(H)— —N— 291(IIa) —H —NO₂ —H —H —OCF₃ —N— —C(H)— 292 (IIa) —H —NO₂ —H —H —F —C(H)——C(H)— 293 (IIa) —H —NO₂ —H —H —F —C(H)— —N— 294 (IIa) —H —NO₂ —H —H —F—N— —C(H)— 295 (IIa) —H —NO₂ —H —CH₃ —H —C(H)— —C(H)— 296 (IIa) —H —NO₂—H —CH₃ —H —C(H)— —N— 297 (IIa) —H —NO₂ —H —CH₃ —H —N— —C(H)— 298 (IIa)—H —NO₂ —H —CH₃ —CH₃ —C(H)— —C(H)— 299 (IIa) —H —NO₂ —H —CH₃ —CH₃ —C(H)——N— 300 (IIa) —H —NO₂ —H —CH₃ —CH₃ —N— —C(H)— 301 (IIa) —H —NO₂ —H —CH₃—OCH₃ —C(H)— —C(H)— 302 (IIa) —H —NO₂ —H —CH₃ —OCH₃ —C(H)— —N— 303 (IIa)—H —NO₂ —H —CH₃ —OCH₃ —N— —C(H)— 304 (IIa) —H —NO₂ —H —CH₃ —OCF₃ —C(H)——C(H)— 305 (IIa) —H —NO₂ —H —CH₃ —OCF₃ —C(H)— —N— 306 (IIa) —H —NO₂ —H—CH₃ —OCF₃ —N— —C(H)— 307 (IIa) —H —NO₂ —H —CH₃ —F —C(H)— —C(H)— 308(IIa) —H —NO₂ —H —CH₃ —F —C(H)— —N— 309 (IIa) —H —NO₂ —H —CH₃ —F —N——C(H)— 310 (IIa) —H —NO₂ —H —OCH₃ —H —C(H)— —C(H)— 311 (IIa) —H —NO₂ —H—OCH₃ —H —C(H)— —N— 312 (IIa) —H —NO₂ —H —OCH₃ —H —N— —C(H)— 313 (IIa)—H —NO₂ —H —OCH₃ —CH₃ —C(H)— —C(H)— 314 (IIa) —H —NO₂ —H —OCH₃ —CH₃—C(H)— —N— 315 (IIa) —H —NO₂ —H —OCH₃ —CH₃ —N— —C(H)— 316 (IIa) —H —NO₂—H —OCH₃ —OCH₃ —C(H)— —C(H)— 317 (IIa) —H —NO₂ —H —OCH₃ —OCH₃ —C(H)— —N—318 (IIa) —H —NO₂ —H —OCH₃ —OCH₃ —N— —C(H)— 319 (IIa) —H —NO₂ —H —OCH₃—OCF₃ —C(H)— —C(H)— 320 (IIa) —H —NO₂ —H —OCH₃ —OCF₃ —C(H)— —N— 321(IIa) —H —NO₂ —H —OCH₃ —OCF₃ —N— —C(H)— 322 (IIa) —H —NO₂ —H —OCH₃ —F—C(H)— —C(H)— 323 (IIa) —H —NO₂ —H —OCH₃ —F —C(H)— —N— 324 (IIa) —H —NO₂—H —OCH₃ —F —N— —C(H)— 325 (IIa) —H —NO₂ —H —NO₂ —H —C(H)— —C(H)— 326(IIa) —H —NO₂ —H —NO₂ —H —C(H)— —N— 327 (IIa) —H —NO₂ —H —NO₂ —H —N——C(H)— 328 (IIa) —H —NO₂ —H —NO₂ —CH₃ —C(H)— —C(H)— 329 (IIa) —H —NO₂ —H—NO₂ —CH₃ —C(H)— —N— 330 (IIa) —H —NO₂ —H —NO₂ —CH₃ —N— —C(H)— 331 (IIa)—H —NO₂ —H —NO₂ —OCH₃ —C(H)— —C(H)— 332 (IIa) —H —NO₂ —H —NO₂ —OCH₃—C(H)— —N— 333 (IIa) —H —NO₂ —H —NO₂ —OCH₃ —N— —C(H)— 334 (IIa) —H —NO₂—H —NO₂ —OCF₃ —C(H)— —C(H)— 335 (IIa) —H —NO₂ —H —NO₂ —OCF₃ —C(H)— —N—336 (IIa) —H —NO₂ —H —NO₂ —OCF₃ —N— —C(H)— 337 (IIa) —H —NO₂ —H —NO₂ —F—C(H)— —C(H)— 338 (IIa) —H —NO₂ —H —NO₂ —F —C(H)— —N— 339 (IIa) —H —NO₂—H —NO₂ —F —N— —C(H)— 340 (IIa) —H —NO₂ —CH₃ —H —H —C(H)— —C(H)— 341(IIa) —H —NO₂ —CH₃ —H —H —C(H)— —N— 342 (IIa) —H —NO₂ —CH₃ —H —H —N——C(H)— 343 (IIa) —H —NO₂ —CH₃ —H —CH₃ —C(H)— —C(H)— 344 (IIa) —H —NO₂—CH₃ —H —CH₃ —C(H)— —N— 345 (IIa) —H —NO₂ —CH₃ —H —CH₃ —N— —C(H)— 346(IIa) —H —NO₂ —CH₃ —H —OCH₃ —C(H)— —C(H)— 347 (IIa) —H —NO₂ —CH₃ —H—OCH₃ —C(H)— —N— 348 (IIa) —H —NO₂ —CH₃ —H —OCH₃ —N— —C(H)— 349 (IIa) —H—NO₂ —CH₃ —H —OCF₃ —C(H)— —C(H)— 350 (IIa) —H —NO₂ —CH₃ —H —OCF₃ —C(H)——N— 351 (IIa) —H —NO₂ —CH₃ —H —OCF₃ —N— —C(H)— 352 (IIa) —H —NO₂ —CH₃ —H—F —C(H)— —C(H)— 353 (IIa) —H —NO₂ —CH₃ —H —F —C(H)— —N— 354 (IIa) —H—NO₂ —CH₃ —H —F —N— —C(H)— 355 (IIa) —H —NO₂ —CH₃ —CH₃ —H —C(H)— —C(H)—356 (IIa) —H —NO₂ —CH₃ —CH₃ —H —C(H)— —N— 357 (IIa) —H —NO₂ —CH₃ —CH₃ —H—N— —C(H)— 358 (IIa) —H —NO₂ —CH₃ —CH₃ —CH₃ —C(H)— —C(H)— 359 (IIa) —H—NO₂ —CH₃ —CH₃ —CH₃ —C(H)— —N— 360 (IIa) —H —NO₂ —CH₃ —CH₃ —CH₃ —N——C(H)— 361 (IIa) —H —NO₂ —CH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 362 (IIa) —H —NO₂—CH₃ —CH₃ —OCH₃ —C(H)— —N— 363 (IIa) —H —NO₂ —CH₃ —CH₃ —OCH₃ —N— —C(H)—364 (IIa) —H —NO₂ —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 365 (IIa) —H —NO₂ —CH₃—CH₃ —OCF₃ —C(H)— —N— 366 (IIa) —H —NO₂ —CH₃ —CH₃ —OCF₃ —N— —C(H)— 367(IIa) —H —NO₂ —CH₃ —CH₃ —F —C(H)— —C(H)— 368 (IIa) —H —NO₂ —CH₃ —CH₃ —F—C(H)— —N— 369 (IIa) —H —NO₂ —CH₃ —CH₃ —F —N— —C(H)— 370 (IIa) —H —NO₂—CH₃ —OCH₃ —H —C(H)— —C(H)— 371 (IIa) —H —NO₂ —CH₃ —OCH₃ —H —C(H)— —N—372 (IIa) —H —NO₂ —CH₃ —OCH₃ —H —N— —C(H)— 373 (IIa) —H —NO₂ —CH₃ —OCH₃—CH₃ —C(H)— —C(H)— 374 (IIa) —H —NO₂ —CH₃ —OCH₃ —CH₃ —C(H)— —N— 375(IIa) —H —NO₂ —CH₃ —OCH₃ —CH₃ —N— —C(H)— 376 (IIa) —H —NO₂ —CH₃ —OCH₃—OCH₃ —C(H)— —C(H)— 377 (IIa) —H —NO₂ —CH₃ —OCH₃ —OCH₃ —C(H)— —N— 378(IIa) —H —NO₂ —CH₃ —OCH₃ —OCH₃ —N— —C(H)— 379 (IIa) —H —NO₂ —CH₃ —OCH₃—OCF₃ —C(H)— —C(H)— 380 (IIa) —H —NO₂ —CH₃ —OCH₃ —OCF₃ —C(H)— —N— 381(IIa) —H —NO₂ —CH₃ —OCH₃ —OCF₃ —N— —C(H)— 382 (IIa) —H —NO₂ —CH₃ —OCH₃—F —C(H)— —C(H)— 383 (IIa) —H —NO₂ —CH₃ —OCH₃ —F —C(H)— —N— 384 (IIa) —H—NO₂ —CH₃ —OCH₃ —F —N— —C(H)— 385 (IIa) —H —NO₂ —CH₃ —NO₂ —H —C(H)——C(H)— 386 (IIa) —H —NO₂ —CH₃ —NO₂ —H —C(H)— —N— 387 (IIa) —H —NO₂ —CH₃—NO₂ —H —N— —C(H)— 388 (IIa) —H —NO₂ —CH₃ —NO₂ —CH₃ —C(H)— —C(H)— 389(IIa) —H —NO₂ —CH₃ —NO₂ —CH₃ —C(H)— —N— 390 (IIa) —H —NO₂ —CH₃ —NO₂ —CH₃—N— —C(H)— 391 (IIa) —H —NO₂ —CH₃ —NO₂ —OCH₃ —C(H)— —C(H)— 392 (IIa) —H—NO₂ —CH₃ —NO₂ —OCH₃ —C(H)— —N— 393 (IIa) —H —NO₂ —CH₃ —NO₂ —OCH₃ —N——C(H)— 394 (IIa) —H —NO₂ —CH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 395 (IIa) —H —NO₂—CH₃ —NO₂ —OCF₃ —C(H)— —N— 396 (IIa) —H —NO₂ —CH₃ —NO₂ —OCF₃ —N— —C(H)—397 (IIa) —H —NO₂ —CH₃ —NO₂ —F —C(H)— —C(H)— 398 (IIa) —H —NO₂ —CH₃ —NO₂—F —C(H)— —N— 399 (IIa) —H —NO₂ —CH₃ —NO₂ —F —N— —C(H)— 400 (IIa) —H—NO₂ —OCH₃ —H —H —C(H)— —C(H)— 401 (IIa) —H —NO₂ —OCH₃ —H —H —C(H)— —N—402 (IIa) —H —NO₂ —OCH₃ —H —H —N— —C(H)— 403 (IIa) —H —NO₂ —OCH₃ —H —CH₃—C(H)— —C(H)— 404 (IIa) —H —NO₂ —OCH₃ —H —CH₃ —C(H)— —N— 405 (IIa) —H—NO₂ —OCH₃ —H —CH₃ —N— —C(H)— 406 (IIa) —H —NO₂ —OCH₃ —H —OCH₃ —C(H)——C(H)— 407 (IIa) —H —NO₂ —OCH₃ —H —OCH₃ —C(H)— —N— 408 (IIa) —H —NO₂—OCH₃ —H —OCH₃ —N— —C(H)— 409 (IIa) —H —NO₂ —OCH₃ —H —OCF₃ —C(H)— —C(H)—410 (IIa) —H —NO₂ —OCH₃ —H —OCF₃ —C(H)— —N— 411 (IIa) —H —NO₂ —OCH₃ —H—OCF₃ —N— —C(H)— 412 (IIa) —H —NO₂ —OCH₃ —H —F —C(H)— —C(H)— 413 (IIa)—H —NO₂ —OCH₃ —H —F —C(H)— —N— 414 (IIa) —H —NO₂ —OCH₃ —H —F —N— —C(H)—415 (IIa) —H —NO₂ —OCH₃ —CH₃ —H —C(H)— —C(H)— 416 (IIa) —H —NO₂ —OCH₃—CH₃ —H —C(H)— —N— 417 (IIa) —H —NO₂ —OCH₃ —CH₃ —H —N— —C(H)— 418 (IIa)—H —NO₂ —OCH₃ —CH₃ —CH₃ —C(H)— —C(H)— 419 (IIa) —H —NO₂ —OCH₃ —CH₃ —CH₃—C(H)— —N— 420 (IIa) —H —NO₂ —OCH₃ —CH₃ —CH₃ —N— —C(H)— 421 (IIa) —H—NO₂ —OCH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 422 (IIa) —H —NO₂ —OCH₃ —CH₃ —OCH₃—C(H)— —N— 423 (IIa) —H —NO₂ —OCH₃ —CH₃ —OCH₃ —N— —C(H)— 424 (IIa) —H—NO₂ —OCH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 425 (IIa) —H —NO₂ —OCH₃ —CH₃ —OCF₃—C(H)— —N— 426 (IIa) —H —NO₂ —OCH₃ —CH₃ —OCF₃ —N— —C(H)— 427 (IIa) —H—NO₂ —OCH₃ —CH₃ —F —C(H)— —C(H)— 428 (IIa) —H —NO₂ —OCH₃ —CH₃ —F —C(H)——N— 429 (IIa) —H —NO₂ —OCH₃ —CH₃ —F —N— —C(H)— 430 (IIa) —H —NO₂ —OCH₃—OCH₃ —H —C(H)— —C(H)— 431 (IIa) —H —NO₂ —OCH₃ —OCH₃ —H —C(H)— —N— 432(IIa) —H —NO₂ —OCH₃ —OCH₃ —H —N— —C(H)— 433 (IIa) —H —NO₂ —OCH₃ —OCH₃—CH₃ —C(H)— —C(H)— 434 (IIa) —H —NO₂ —OCH₃ —OCH₃ —CH₃ —C(H)— —N— 435(IIa) —H —NO₂ —OCH₃ —OCH₃ —CH₃ —N— —C(H)— 436 (IIa) —H —NO₂ —OCH₃ —OCH₃—OCH₃ —C(H)— —C(H)— 437 (IIa) —H —NO₂ —OCH₃ —OCH₃ —OCH₃ —C(H)— —N— 438(IIa) —H —NO₂ —OCH₃ —OCH₃ —OCH₃ —N— —C(H)— 439 (IIa) —H —NO₂ —OCH₃ —OCH₃—OCF₃ —C(H)— —C(H)— 440 (IIa) —H —NO₂ —OCH₃ —OCH₃ —OCF₃ —C(H)— —N— 441(IIa) —H —NO₂ —OCH₃ —OCH₃ —OCF₃ —N— —C(H)— 442 (IIa) —H —NO₂ —OCH₃ —OCH₃—F —C(H)— —C(H)— 443 (IIa) —H —NO₂ —OCH₃ —OCH₃ —F —C(H)— —N— 444 (IIa)—H —NO₂ —OCH₃ —OCH₃ —F —N— —C(H)— 445 (IIa) —H —NO₂ —OCH₃ —NO₂ —H —C(H)——C(H)— 446 (IIa) —H —NO₂ —OCH₃ —NO₂ —H —C(H)— —N— 447 (IIa) —H —NO₂—OCH₃ —NO₂ —H —N— —C(H)— 448 (IIa) —H —NO₂ —OCH₃ —NO₂ —CH₃ —C(H)— —C(H)—449 (IIa) —H —NO₂ —OCH₃ —NO₂ —CH₃ —C(H)— —N— 450 (IIa) —H —NO₂ —OCH₃—NO₂ —CH₃ —N— —C(H)— 451 (IIa) —H —NO₂ —OCH₃ —NO₂ —OCH₃ —C(H)— —C(H)—452 (IIa) —H —NO₂ —OCH₃ —NO₂ —OCH₃ —C(H)— —N— 453 (IIa) —H —NO₂ —OCH₃—NO₂ —OCH₃ —N— —C(H)— 454 (IIa) —H —NO₂ —OCH₃ —NO₂ —OCF₃ —C(H)— —C(H)—455 (IIa) —H —NO₂ —OCH₃ —NO₂ —OCF₃ —C(H)— —N— 456 (IIa) —H —NO₂ —OCH₃—NO₂ —OCF₃ —N— —C(H)— 457 (IIa) —H —NO₂ —OCH₃ —NO₂ —F —C(H)— —C(H)— 458(IIa) —H —NO₂ —OCH₃ —NO₂ —F —C(H)— —N— 459 (IIa) —H —NO₂ —OCH₃ —NO₂ —F—N— —C(H)— 460 (IIa) —H —OCH₃ —H —H —H —C(H)— —C(H)— 461 (IIa) —H —OCH₃—H —H —H —C(H)— —N— 462 (IIa) —H —OCH₃ —H —H —H —N— —C(H)— 463 (IIa) —H—OCH₃ —H —H —CH₃ —C(H)— —C(H)— 464 (IIa) —H —OCH₃ —H —H —CH₃ —C(H)— —N—465 (IIa) —H —OCH₃ —H —H —CH₃ —N— —C(H)— 466 (IIa) —H —OCH₃ —H —H —OCH₃—C(H)— —C(H)— 467 (IIa) —H —OCH₃ —H —H —OCH₃ —C(H)— —N— 468 (IIa) —H—OCH₃ —H —H —OCH₃ —N— —C(H)— 469 (IIa) —H —OCH₃ —H —H —OCF₃ —C(H)——C(H)— 470 (IIa) —H —OCH₃ —H —H —OCF₃ —C(H)— —N— 471 (IIa) —H —OCH₃ —H—H —OCF₃ —N— —C(H)— 472 (IIa) —H —OCH₃ —H —H —F —C(H)— —C(H)— 473 (IIa)—H —OCH₃ —H —H —F —C(H)— —N— 474 (IIa) —H —OCH₃ —H —H —F —N— —C(H)— 475(IIa) —H —OCH₃ —H —CH₃ —H —C(H)— —C(H)— 476 (IIa) —H —OCH₃ —H —CH₃ —H—C(H)— —N— 477 (IIa) —H —OCH₃ —H —CH₃ —H —N— —C(H)— 478 (IIa) —H —OCH₃—H —CH₃ —CH₃ —C(H)— —C(H)— 479 (IIa) —H —OCH₃ —H —CH₃ —CH₃ —C(H)— —N—480 (IIa) —H —OCH₃ —H —CH₃ —CH₃ —N— —C(H)— 481 (IIa) —H —OCH₃ —H —CH₃—OCH₃ —C(H)— —C(H)— 482 (IIa) —H —OCH₃ —H —CH₃ —OCH₃ —C(H)— —N— 483(IIa) —H —OCH₃ —H —CH₃ —OCH₃ —N— —C(H)— 484 (IIa) —H —OCH₃ —H —CH₃ —OCF₃—C(H)— —C(H)— 485 (IIa) —H —OCH₃ —H —CH₃ —OCF₃ —C(H)— —N— 486 (IIa) —H—OCH₃ —H —CH₃ —OCF₃ —N— —C(H)— 487 (IIa) —H —OCH₃ —H —CH₃ —F —C(H)——C(H)— 488 (IIa) —H —OCH₃ —H —CH₃ —F —C(H)— —N— 489 (IIa) —H —OCH₃ —H—CH₃ —F —N— —C(H)— 490 (IIa) —H —OCH₃ —H —OCH₃ —H —C(H)— —C(H)— 491(IIa) —H —OCH₃ —H —OCH₃ —H —C(H)— —N— 492 (IIa) —H —OCH₃ —H —OCH₃ —H —N——C(H)— 493 (IIa) —H —OCH₃ —H —OCH₃ —CH₃ —C(H)— —C(H)— 494 (IIa) —H —OCH₃—H —OCH₃ —CH₃ —C(H)— —N— 495 (IIa) —H —OCH₃ —H —OCH₃ —CH₃ —N— —C(H)— 496(IIa) —H —OCH₃ —H —OCH₃ —OCH₃ —C(H)— —C(H)— 497 (IIa) —H —OCH₃ —H —OCH₃—OCH₃ —C(H)— —N— 498 (IIa) —H —OCH₃ —H —OCH₃ —OCH₃ —N— —C(H)— 499 (IIa)—H —OCH₃ —H —OCH₃ —OCF₃ —C(H)— —C(H)— 500 (IIa) —H —OCH₃ —H —OCH₃ —OCF₃—C(H)— —N— 501 (IIa) —H —OCH₃ —H —OCH₃ —OCF₃ —N— —C(H)— 502 (IIa) —H—OCH₃ —H —OCH₃ —F —C(H)— —C(H)— 503 (IIa) —H —OCH₃ —H —OCH₃ —F —C(H)——N— 504 (IIa) —H —OCH₃ —H —OCH₃ —F —N— —C(H)— 505 (IIa) —H —OCH₃ —H —NO₂—H —C(H)— —C(H)— 506 (IIa) —H —OCH₃ —H —NO₂ —H —C(H)— —N— 507 (IIa) —H—OCH₃ —H —NO₂ —H —N— —C(H)— 508 (IIa) —H —OCH₃ —H —NO₂ —CH₃ —C(H)——C(H)— 509 (IIa) —H —OCH₃ —H —NO₂ —CH₃ —C(H)— —N— 510 (IIa) —H —OCH₃ —H—NO₂ —CH₃ —N— —C(H)— 511 (IIa) —H —OCH₃ —H —NO₂ —OCH₃ —C(H)— —C(H)— 512(IIa) —H —OCH₃ —H —NO₂ —OCH₃ —C(H)— —N— 513 (IIa) —H —OCH₃ —H —NO₂ —OCH₃—N— —C(H)— 514 (IIa) —H —OCH₃ —H —NO₂ —OCF₃ —C(H)— —C(H)— 515 (IIa) —H—OCH₃ —H —NO₂ —OCF₃ —C(H)— —N— 516 (IIa) —H —OCH₃ —H —NO₂ —OCF₃ —N——C(H)— 517 (IIa) —H —OCH₃ —H —NO₂ —F —C(H)— —C(H)— 518 (IIa) —H —OCH₃ —H—NO₂ —F —C(H)— —N— 519 (IIa) —H —OCH₃ —H —NO₂ —F —N— —C(H)— 520 (IIa) —H—OCH₃ —CH₃ —H —H —C(H)— —C(H)— 521 (IIa) —H —OCH₃ —CH₃ —H —H —C(H)— —N—522 (IIa) —H —OCH₃ —CH₃ —H —H —N— —C(H)— 523 (IIa) —H —OCH₃ —CH₃ —H —CH₃—C(H)— —C(H)— 524 (IIa) —H —OCH₃ —CH₃ —H —CH₃ —C(H)— —N— 525 (IIa) —H—OCH₃ —CH₃ —H —CH₃ —N— —C(H)— 526 (IIa) —H —OCH₃ —CH₃ —H —OCH₃ —C(H)——C(H)— 527 (IIa) —H —OCH₃ —CH₃ —H —OCH₃ —C(H)— —N— 528 (IIa) —H —OCH₃—CH₃ —H —OCH₃ —N— —C(H)— 529 (IIa) —H —OCH₃ —CH₃ —H —OCF₃ —C(H)— —C(H)—530 (IIa) —H —OCH₃ —CH₃ —H —OCF₃ —C(H)— —N— 531 (IIa) —H —OCH₃ —CH₃ —H—OCF₃ —N— —C(H)— 532 (IIa) —H —OCH₃ —CH₃ —H —F —C(H)— —C(H)— 533 (IIa)—H —OCH₃ —CH₃ —H —F —C(H)— —N— 534 (IIa) —H —OCH₃ —CH₃ —H —F —N— —C(H)—535 (IIa) —H —OCH₃ —CH₃ —CH₃ —H —C(H)— —C(H)— 536 (IIa) —H —OCH₃ —CH₃—CH₃ —H —C(H)— —N— 537 (IIa) —H —OCH₃ —CH₃ —CH₃ —H —N— —C(H)— 538 (IIa)—H —OCH₃ —CH₃ —CH₃ —CH₃ —C(H)— —C(H)— 539 (IIa) —H —OCH₃ —CH₃ —CH₃ —CH₃—C(H)— —N— 540 (IIa) —H —OCH₃ —CH₃ —CH₃ —CH₃ —N— —C(H)— 541 (IIa) —H—OCH₃ —CH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 542 (IIa) —H —OCH₃ —CH₃ —CH₃ —OCH₃—C(H)— —N— 543 (IIa) —H —OCH₃ —CH₃ —CH₃ —OCH₃ —N— —C(H)— 544 (IIa) —H—OCH₃ —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 545 (IIa) —H —OCH₃ —CH₃ —CH₃ —OCF₃—C(H)— —N— 546 (IIa) —H —OCH₃ —CH₃ —CH₃ —OCF₃ —N— —C(H)— 547 (IIa) —H—OCH₃ —CH₃ —CH₃ —F —C(H)— —C(H)— 548 (IIa) —H —OCH₃ —CH₃ —CH₃ —F —C(H)——N— 549 (IIa) —H —OCH₃ —CH₃ —CH₃ —F —N— —C(H)— 550 (IIa) —H —OCH₃ —CH₃—OCH₃ —H —C(H)— —C(H)— 551 (IIa) —H —OCH₃ —CH₃ —OCH₃ —H —C(H)— —N— 552(IIa) —H —OCH₃ —CH₃ —OCH₃ —H —N— —C(H)— 553 (IIa) —H —OCH₃ —CH₃ —OCH₃—CH₃ —C(H)— —C(H)— 554 (IIa) —H —OCH₃ —CH₃ —OCH₃ —CH₃ —C(H)— —N— 555(IIa) —H —OCH₃ —CH₃ —OCH₃ —CH₃ —N— —C(H)— 556 (IIa) —H —OCH₃ —CH₃ —OCH₃—OCH₃ —C(H)— —C(H)— 557 (IIa) —H —OCH₃ —CH₃ —OCH₃ —OCH₃ —C(H)— —N— 558(IIa) —H —OCH₃ —CH₃ —OCH₃ —OCH₃ —N— —C(H)— 559 (IIa) —H —OCH₃ —CH₃ —OCH₃—OCF₃ —C(H)— —C(H)— 560 (IIa) —H —OCH₃ —CH₃ —OCH₃ —OCF₃ —C(H)— —N— 561(IIa) —H —OCH₃ —CH₃ —OCH₃ —OCF₃ —N— —C(H)— 562 (IIa) —H —OCH₃ —CH₃ —OCH₃—F —C(H)— —C(H)— 563 (IIa) —H —OCH₃ —CH₃ —OCH₃ —F —C(H)— —N— 564 (IIa)—H —OCH₃ —CH₃ —OCH₃ —F —N— —C(H)— 565 (IIa) —H —OCH₃ —CH₃ —NO₂ —H —C(H)——C(H)— 566 (IIa) —H —OCH₃ —CH₃ —NO₂ —H —C(H)— —N— 567 (IIa) —H —OCH₃—CH₃ —NO₂ —H —N— —C(H)— 568 (IIa) —H —OCH₃ —CH₃ —NO₂ —CH₃ —C(H)— —C(H)—569 (IIa) —H —OCH₃ —CH₃ —NO₂ —CH₃ —C(H)— —N— 570 (IIa) —H —OCH₃ —CH₃—NO₂ —CH₃ —N— —C(H)— 571 (IIa) —H —OCH₃ —CH₃ —NO₂ —OCH₃ —C(H)— —C(H)—572 (IIa) —H —OCH₃ —CH₃ —NO₂ —OCH₃ —C(H)— —N— 573 (IIa) —H —OCH₃ —CH₃—NO₂ —OCH₃ —N— —C(H)— 574 (IIa) —H —OCH₃ —CH₃ —NO₂ —OCF₃ —C(H)— —C(H)—575 (IIa) —H —OCH₃ —CH₃ —NO₂ —OCF₃ —C(H)— —N— 576 (IIa) —H —OCH₃ —CH₃—NO₂ —OCF₃ —N— —C(H)— 577 (IIa) —H —OCH₃ —CH₃ —NO₂ —F —C(H)— —C(H)— 578(IIa) —H —OCH₃ —CH₃ —NO₂ —F —C(H)— —N— 579 (IIa) —H —OCH₃ —CH₃ —NO₂ —F—N— —C(H)— 580 (IIa) —H —OCH₃ —OCH₃ —H —H —C(H)— —C(H)— 581 (IIa) —H—OCH₃ —OCH₃ —H —H —C(H)— —N— 582 (IIa) —H —OCH₃ —OCH₃ —H —H —N— —C(H)—583 (IIa) —H —OCH₃ —OCH₃ —H —CH₃ —C(H)— —C(H)— 584 (IIa) —H —OCH₃ —OCH₃—H —CH₃ —C(H)— —N— 585 (IIa) —H —OCH₃ —OCH₃ —H —CH₃ —N— —C(H)— 586 (IIa)—H —OCH₃ —OCH₃ —H —OCH₃ —C(H)— —C(H)— 587 (IIa) —H —OCH₃ —OCH₃ —H —OCH₃—C(H)— —N— 588 (IIa) —H —OCH₃ —OCH₃ —H —OCH₃ —N— —C(H)— 589 (IIa) —H—OCH₃ —OCH₃ —H —OCF₃ —C(H)— —C(H)— 590 (IIa) —H —OCH₃ —OCH₃ —H —OCF₃—C(H)— —N— 591 (IIa) —H —OCH₃ —OCH₃ —H —OCF₃ —N— —C(H)— 592 (IIa) —H—OCH₃ —OCH₃ —H —F —C(H)— —C(H)— 593 (IIa) —H —OCH₃ —OCH₃ —H —F —C(H)——N— 594 (IIa) —H —OCH₃ —OCH₃ —H —F —N— —C(H)— 595 (IIa) —H —OCH₃ —OCH₃—CH₃ —H —C(H)— —C(H)— 596 (IIa) —H —OCH₃ —OCH₃ —CH₃ —H —C(H)— —N— 597(IIa) —H —OCH₃ —OCH₃ —CH₃ —H —N— —C(H)— 598 (IIa) —H —OCH₃ —OCH₃ —CH₃—CH₃ —C(H)— —C(H)— 599 (IIa) —H —OCH₃ —OCH₃ —CH₃ —CH₃ —C(H)— —N— 600(IIa) —H —OCH₃ —OCH₃ —CH₃ —CH₃ —N— —C(H)— 601 (IIa) —H —OCH₃ —OCH₃ —CH₃—OCH₃ —C(H)— —C(H)— 602 (IIa) —H —OCH₃ —OCH₃ —CH₃ —OCH₃ —C(H)— —N— 603(IIa) —H —OCH₃ —OCH₃ —CH₃ —OCH₃ —N— —C(H)— 604 (IIa) —H —OCH₃ —OCH₃ —CH₃—OCF₃ —C(H)— —C(H)— 605 (IIa) —H —OCH₃ —OCH₃ —CH₃ —OCF₃ —C(H)— —N— 606(IIa) —H —OCH₃ —OCH₃ —CH₃ —OCF₃ —N— —C(H)— 607 (IIa) —H —OCH₃ —OCH₃ —CH₃—F —C(H)— —C(H)— 608 (IIa) —H —OCH₃ —OCH₃ —CH₃ —F —C(H)— —N— 609 (IIa)—H —OCH₃ —OCH₃ —CH₃ —F —N— —C(H)— 610 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —H—C(H)— —C(H)— 611 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —H —C(H)— —N— 612 (IIa) —H—OCH₃ —OCH₃ —OCH₃ —H —N— —C(H)— 613 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —CH₃—C(H)— —C(H)— 614 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —CH₃ —C(H)— —N— 615 (IIa)—H —OCH₃ —OCH₃ —OCH₃ —CH₃ —N— —C(H)— 616 (IIa) —H —OCH₃ —OCH₃ —OCH₃—OCH₃ —C(H)— —C(H)— 617 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —OCH₃ —C(H)— —N— 618(IIa) —H —OCH₃ —OCH₃ —OCH₃ —OCH₃ —N— —C(H)— 619 (IIa) —H —OCH₃ —OCH₃—OCH₃ —OCF₃ —C(H)— —C(H)— 620 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —OCF₃ —C(H)——N— 621 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —OCF₃ —N— —C(H)— 622 (IIa) —H —OCH₃—OCH₃ —OCH₃ —F —C(H)— —C(H)— 623 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —F —C(H)——N— 624 (IIa) —H —OCH₃ —OCH₃ —OCH₃ —F —N— —C(H)— 625 (IIa) —H —OCH₃—OCH₃ —NO₂ —H —C(H)— —C(H)— 626 (IIa) —H —OCH₃ —OCH₃ —NO₂ —H —C(H)— —N—627 (IIa) —H —OCH₃ —OCH₃ —NO₂ —H —N— —C(H)— 628 (IIa) —H —OCH₃ —OCH₃—NO₂ —CH₃ —C(H)— —C(H)— 629 (IIa) —H —OCH₃ —OCH₃ —NO₂ —CH₃ —C(H)— —N—630 (IIa) —H —OCH₃ —OCH₃ —NO₂ —CH₃ —N— —C(H)— 631 (IIa) —H —OCH₃ —OCH₃—NO₂ —OCH₃ —C(H)— —C(H)— 632 (IIa) —H —OCH₃ —OCH₃ —NO₂ —OCH₃ —C(H)— —N—633 (IIa) —H —OCH₃ —OCH₃ —NO₂ —OCH₃ —N— —C(H)— 634 (IIa) —H —OCH₃ —OCH₃—NO₂ —OCF₃ —C(H)— —C(H)— 635 (IIa) —H —OCH₃ —OCH₃ —NO₂ —OCF₃ —C(H)— —N—636 (IIa) —H —OCH₃ —OCH₃ —NO₂ —OCF₃ —N— —C(H)— 637 (IIa) —H —OCH₃ —OCH₃—NO₂ —F —C(H)— —C(H)— 638 (IIa) —H —OCH₃ —OCH₃ —NO₂ —F —C(H)— —N— 639(IIa) —H —OCH₃ —OCH₃ —NO₂ —F —N— —C(H)— 640 (IIa) or (IIb) —CH₃ —H —H —H—H —C(H)— —C(H)— 641 (IIa) or (IIb) —CH₃ —H —H —H —H —C(H)— —N— 642(IIa) or (IIb) —CH₃ —H —H —H —H —N— —C(H)— 643 (IIa) or (IIb) —CH₃ —H —H—H —CH₃ —C(H)— —C(H)— 644 (IIa) or (IIb) —CH₃ —H —H —H —CH₃ —C(H)— —N—645 (IIa) or (IIb) —CH₃ —H —H —H —CH₃ —N— —C(H)— 646 (IIa) or (IIb) —CH₃—H —H —H —OCH₃ —C(H)— —C(H)— 647 (IIa) or (IIb) —CH₃ —H —H —H —OCH₃—C(H)— —N— 648 (IIa) or (IIb) —CH₃ —H —H —H —OCH₃ —N— —C(H)— 649 (IIa)or (IIb) —CH₃ —H —H —H —OCF₃ —C(H)— —C(H)— 650 (IIa) or (IIb) —CH₃ —H —H—H —OCF₃ —C(H)— —N— 651 (IIa) or (IIb) —CH₃ —H —H —H —OCF₃ —N— —C(H)—652 (IIa) or (IIb) —CH₃ —H —H —H —F —C(H)— —C(H)— 653 (IIa) or (IIb)—CH₃ —H —H —H —F —C(H)— —N— 654 (IIa) or (IIb) —CH₃ —H —H —H —F —N——C(H)— 655 (IIa) or (IIb) —CH₃ —H —H —CH₃ —H —C(H)— —C(H)— 656 (IIa) or(IIb) —CH₃ —H —H —CH₃ —H —C(H)— —N— 657 (IIa) or (IIb) —CH₃ —H —H —CH₃—H —N— —C(H)— 658 (IIa) or (IIb) —CH₃ —H —H —CH₃ —CH₃ —C(H)— —C(H)— 659(IIa) or (IIb) —CH₃ —H —H —CH₃ —CH₃ —C(H)— —N— 660 (IIa) or (IIb) —CH₃—H —H —CH₃ —CH₃ —N— —C(H)— 661 (IIa) or (IIb) —CH₃ —H —H —CH₃ —OCH₃—C(H)— —C(H)— 662 (IIa) or (IIb) —CH₃ —H —H —CH₃ —OCH₃ —C(H)— —N— 663(IIa) or (IIb) —CH₃ —H —H —CH₃ —OCH₃ —N— —C(H)— 664 (IIa) or (IIb) —CH₃—H —H —CH₃ —OCF₃ —C(H)— —C(H)— 665 (IIa) or (IIb) —CH₃ —H —H —CH₃ —OCF₃—C(H)— —N— 666 (IIa) or (IIb) —CH₃ —H —H —CH₃ —OCF₃ —N— —C(H)— 667 (IIa)or (IIb) —CH₃ —H —H —CH₃ —F —C(H)— —C(H)— 668 (IIa) or (IIb) —CH₃ —H —H—CH₃ —F —C(H)— —N— 669 (IIa) or (IIb) —CH₃ —H —H —CH₃ —F —N— —C(H)— 670(IIa) or (IIb) —CH₃ —H —H —OCH₃ —H —C(H)— —C(H)— 671 (IIa) or (IIb) —CH₃—H —H —OCH₃ —H —C(H)— —N— 672 (IIa) or (IIb) —CH₃ —H —H —OCH₃ —H —N——C(H)— 673 (IIa) or (IIb) —CH₃ —H —H —OCH₃ —CH₃ —C(H)— —C(H)— 674 (IIa)or (IIb) —CH₃ —H —H —OCH₃ —CH₃ —C(H)— —N— 675 (IIa) or (IIb) —CH₃ —H —H—OCH₃ —CH₃ —N— —C(H)— 676 (IIa) or (IIb) —CH₃ —H —H —OCH₃ —OCH₃ —C(H)——C(H)— 677 (IIa) or (IIb) —CH₃ —H —H —OCH₃ —OCH₃ —C(H)— —N— 678 (IIa) or(IIb) —CH₃ —H —H —OCH₃ —OCH₃ —N— —C(H)— 679 (IIa) or (IIb) —CH₃ —H —H—OCH₃ —OCF₃ —C(H)— —C(H)— 680 (IIa) or (IIb) —CH₃ —H —H —OCH₃ —OCF₃—C(H)— —N— 681 (IIa) or (IIb) —CH₃ —H —H —OCH₃ —OCF₃ —N— —C(H)— 682(IIa) or (IIb) —CH₃ —H —H —OCH₃ —F —C(H)— —C(H)— 683 (IIa) or (IIb) —CH₃—H —H —OCH₃ —F —C(H)— —N— 684 (IIa) or (IIb) —CH₃ —H —H —OCH₃ —F —N——C(H)— 685 (IIa) or (IIb) —CH₃ —H —H —NO₂ —H —C(H)— —C(H)— 686 (IIa) or(IIb) —CH₃ —H —H —NO₂ —H —C(H)— —N— 687 (IIa) or (IIb) —CH₃ —H —H —NO₂—H —N— —C(H)— 688 (IIa) or (IIb) —CH₃ —H —H —NO₂ —CH₃ —C(H)— —C(H)— 689(IIa) or (IIb) —CH₃ —H —H —NO₂ —CH₃ —C(H)— —N— 690 (IIa) or (IIb) —CH₃—H —H —NO₂ —CH₃ —N— —C(H)— 691 (IIa) or (IIb) —CH₃ —H —H —NO₂ —OCH₃—C(H)— —C(H)— 692 (IIa) or (IIb) —CH₃ —H —H —NO₂ —OCH₃ —C(H)— —N— 693(IIa) or (IIb) —CH₃ —H —H —NO₂ —OCH₃ —N— —C(H)— 694 (IIa) or (IIb) —CH₃—H —H —NO₂ —OCF₃ —C(H)— —C(H)— 695 (IIa) or (IIb) —CH₃ —H —H —NO₂ —OCF₃—C(H)— —N— 696 (IIa) or (IIb) —CH₃ —H —H —NO₂ —OCF₃ —N— —C(H)— 697 (IIa)or (IIb) —CH₃ —H —H —NO₂ —F —C(H)— —C(H)— 698 (IIa) or (IIb) —CH₃ —H —H—NO₂ —F —C(H)— —N— 699 (IIa) or (IIb) —CH₃ —H —H —NO₂ —F —N— —C(H)— 700(IIa) or (IIb) —CH₃ —H —CH₃ —H —H —C(H)— —C(H)— 701 (IIa) or (IIb) —CH₃—H —CH₃ —H —H —C(H)— —N— 702 (IIa) or (IIb) —CH₃ —H —CH₃ —H —H —N——C(H)— 703 (IIa) or (IIb) —CH₃ —H —CH₃ —H —CH₃ —C(H)— —C(H)— 704 (IIa)or (IIb) —CH₃ —H —CH₃ —H —CH₃ —C(H)— —N— 705 (IIa) or (IIb) —CH₃ —H —CH₃—H —CH₃ —N— —C(H)— 706 (IIa) or (IIb) —CH₃ —H —CH₃ —H —OCH₃ —C(H)——C(H)— 707 (IIa) or (IIb) —CH₃ —H —CH₃ —H —OCH₃ —C(H)— —N— 708 (IIa) or(IIb) —CH₃ —H —CH₃ —H —OCH₃ —N— —C(H)— 709 (IIa) or (IIb) —CH₃ —H —CH₃—H —OCF₃ —C(H)— —C(H)— 710 (IIa) or (IIb) —CH₃ —H —CH₃ —H —OCF₃ —C(H)——N— 711 (IIa) or (IIb) —CH₃ —H —CH₃ —H —OCF₃ —N— —C(H)— 712 (IIa) or(IIb) —CH₃ —H —CH₃ —H —F —C(H)— —C(H)— 713 (IIa) or (IIb) —CH₃ —H —CH₃—H —F —C(H)— —N— 714 (IIa) or (IIb) —CH₃ —H —CH₃ —H —F —N— —C(H)— 715(IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —H —C(H)— —C(H)— 716 (IIa) or (IIb)—CH₃ —H —CH₃ —CH₃ —H —C(H)— —N— 717 (IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —H—N— —C(H)— 718 (IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —CH₃ —C(H)— —C(H)— 719(IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —CH₃ —C(H)— —N— 720 (IIa) or (IIb) —CH₃—H —CH₃ —CH₃ —CH₃ —N— —C(H)— 721 (IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —OCH₃—C(H)— —C(H)— 722 (IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —OCH₃ —C(H)— —N— 723(IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —OCH₃ —N— —C(H)— 724 (IIa) or (IIb)—CH₃ —H —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 725 (IIa) or (IIb) —CH₃ —H —CH₃—CH₃ —OCF₃ —C(H)— —N— 726 (IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —OCF₃ —N——C(H)— 727 (IIa) or (IIb) —CH₃ —H —CH₃ —CH₃ —F —C(H)— —C(H)— 728 (IIa)or (IIb) —CH₃ —H —CH₃ —CH₃ —F —C(H)— —N— 729 (IIa) or (IIb) —CH₃ —H —CH₃—CH₃ —F —N— —C(H)— 730 (IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —H —C(H)——C(H)— 731 (IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —H —C(H)— —N— 732 (IIa) or(IIb) —CH₃ —H —CH₃ —OCH₃ —H —N— —C(H)— 733 (IIa) or (IIb) —CH₃ —H —CH₃—OCH₃ —CH₃ —C(H)— —C(H)— 734 (IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —CH₃—C(H)— —N— 735 (IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —CH₃ —N— —C(H)— 736(IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —OCH₃ —C(H)— —C(H)— 737 (IIa) or (IIb)—CH₃ —H —CH₃ —OCH₃ —OCH₃ —C(H)— —N— 738 (IIa) or (IIb) —CH₃ —H —CH₃—OCH₃ —OCH₃ —N— —C(H)— 739 (IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —OCF₃—C(H)— —C(H)— 740 (IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —OCF₃ —C(H)— —N— 741(IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —OCF₃ —N— —C(H)— 742 (IIa) or (IIb)—CH₃ —H —CH₃ —OCH₃ —F —C(H)— —C(H)— 743 (IIa) or (IIb) —CH₃ —H —CH₃—OCH₃ —F —C(H)— —N— 744 (IIa) or (IIb) —CH₃ —H —CH₃ —OCH₃ —F —N— —C(H)—745 (IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —H —C(H)— —C(H)— 746 (IIa) or (IIb)—CH₃ —H —CH₃ —NO₂ —H —C(H)— —N— 747 (IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —H—N— —C(H)— 748 (IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —CH₃ —C(H)— —C(H)— 749(IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —CH₃ —C(H)— —N— 750 (IIa) or (IIb) —CH₃—H —CH₃ —NO₂ —CH₃ —N— —C(H)— 751 (IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —OCH₃—C(H)— —C(H)— 752 (IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —OCH₃ —C(H)— —N— 753(IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —OCH₃ —N— —C(H)— 754 (IIa) or (IIb)—CH₃ —H —CH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 755 (IIa) or (IIb) —CH₃ —H —CH₃—NO₂ —OCF₃ —C(H)— —N— 756 (IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —OCF₃ —N——C(H)— 757 (IIa) or (IIb) —CH₃ —H —CH₃ —NO₂ —F —C(H)— —C(H)— 758 (IIa)or (IIb) —CH₃ —H —CH₃ —NO₂ —F —C(H)— —N— 759 (IIa) or (IIb) —CH₃ —H —CH₃—NO₂ —F —N— —C(H)— 760 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —H —C(H)— —C(H)—761 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —H —C(H)— —N— 762 (IIa) or (IIb)—CH₃ —H —OCH₃ —H —H —N— —C(H)— 763 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —CH₃—C(H)— —C(H)— 764 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —CH₃ —C(H)— —N— 765(IIa) or (IIb) —CH₃ —H —OCH₃ —H —CH₃ —N— —C(H)— 766 (IIa) or (IIb) —CH₃—H —OCH₃ —H —OCH₃ —C(H)— —C(H)— 767 (IIa) or (IIb) —CH₃ —H —OCH₃ —H—OCH₃ —C(H)— —N— 768 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —OCH₃ —N— —C(H)—769 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —OCF₃ —C(H)— —C(H)— 770 (IIa) or(IIb) —CH₃ —H —OCH₃ —H —OCF₃ —C(H)— —N— 771 (IIa) or (IIb) —CH₃ —H —OCH₃—H —OCF₃ —N— —C(H)— 772 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —F —C(H)— —C(H)—773 (IIa) or (IIb) —CH₃ —H —OCH₃ —H —F —C(H)— —N— 774 (IIa) or (IIb)—CH₃ —H —OCH₃ —H —F —N— —C(H)— 775 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —H—C(H)— —C(H)— 776 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —H —C(H)— —N— 777(IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —H —N— —C(H)— 778 (IIa) or (IIb) —CH₃—H —OCH₃ —CH₃ —CH₃ —C(H)— —C(H)— 779 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃—CH₃ —C(H)— —N— 780 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —CH₃ —N— —C(H)—781 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 782 (IIa) or(IIb) —CH₃ —H —OCH₃ —CH₃ —OCH₃ —C(H)— —N— 783 (IIa) or (IIb) —CH₃ —H—OCH₃ —CH₃ —OCH₃ —N— —C(H)— 784 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —OCF₃—C(H)— —C(H)— 785 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —OCF₃ —C(H)— —N— 786(IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —OCF₃ —N— —C(H)— 787 (IIa) or (IIb)—CH₃ —H —OCH₃ —CH₃ —F —C(H)— —C(H)— 788 (IIa) or (IIb) —CH₃ —H —OCH₃—CH₃ —F —C(H)— —N— 789 (IIa) or (IIb) —CH₃ —H —OCH₃ —CH₃ —F —N— —C(H)—790 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —H —C(H)— —C(H)— 791 (IIa) or(IIb) —CH₃ —H —OCH₃ —OCH₃ —H —C(H)— —N— 792 (IIa) or (IIb) —CH₃ —H —OCH₃—OCH₃ —H —N— —C(H)— 793 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —CH₃ —C(H)——C(H)— 794 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —CH₃ —C(H)— —N— 795 (IIa)or (IIb) —CH₃ —H —OCH₃ —OCH₃ —CH₃ —N— —C(H)— 796 (IIa) or (IIb) —CH₃ —H—OCH₃ —OCH₃ —OCH₃ —C(H)— —C(H)— 797 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃—OCH₃ —C(H)— —N— 798 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —OCH₃ —N— —C(H)—799 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —OCF₃ —C(H)— —C(H)— 800 (IIa) or(IIb) —CH₃ —H —OCH₃ —OCH₃ —OCF₃ —C(H)— —N— 801 (IIa) or (IIb) —CH₃ —H—OCH₃ —OCH₃ —OCF₃ —N— —C(H)— 802 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —F—C(H)— —C(H)— 803 (IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —F —C(H)— —N— 804(IIa) or (IIb) —CH₃ —H —OCH₃ —OCH₃ —F —N— —C(H)— 805 (IIa) or (IIb) —CH₃—H —OCH₃ —NO₂ —H —C(H)— —C(H)— 806 (IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —H—C(H)— —N— 807 (IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —H —N— —C(H)— 808 (IIa)or (IIb) —CH₃ —H —OCH₃ —NO₂ —CH₃ —C(H)— —C(H)— 809 (IIa) or (IIb) —CH₃—H —OCH₃ —NO₂ —CH₃ —C(H)— —N— 810 (IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —CH₃—N— —C(H)— 811 (IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —OCH₃ —C(H)— —C(H)— 812(IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —OCH₃ —C(H)— —N— 813 (IIa) or (IIb)—CH₃ —H —OCH₃ —NO₂ —OCH₃ —N— —C(H)— 814 (IIa) or (IIb) —CH₃ —H —OCH₃—NO₂ —OCF₃ —C(H)— —C(H)— 815 (IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —OCF₃—C(H)— —N— 816 (IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —OCF₃ —N— —C(H)— 817(IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂ —F —C(H)— —C(H)— 818 (IIa) or (IIb)—CH₃ —H —OCH₃ —NO₂ —F —C(H)— —N— 819 (IIa) or (IIb) —CH₃ —H —OCH₃ —NO₂—F —N— —C(H)— 820 (IIa) or (IIb) —CH₃ —NO₂ —H —H —H —C(H)— —C(H)— 821(IIa) or (IIb) —CH₃ —NO₂ —H —H —H —C(H)— —N— 822 (IIa) or (IIb) —CH₃—NO₂ —H —H —H —N— —C(H)— 823 (IIa) or (IIb) —CH₃ —NO₂ —H —H —CH₃ —C(H)——C(H)— 824 (IIa) or (IIb) —CH₃ —NO₂ —H —H —CH₃ —C(H)— —N— 825 (IIa) or(IIb) —CH₃ —NO₂ —H —H —CH₃ —N— —C(H)— 826 (IIa) or (IIb) —CH₃ —NO₂ —H —H—OCH₃ —C(H)— —C(H)— 827 (IIa) or (IIb) —CH₃ —NO₂ —H —H —OCH₃ —C(H)— —N—828 (IIa) or (IIb) —CH₃ —NO₂ —H —H —OCH₃ —N— —C(H)— 829 (IIa) or (IIb)—CH₃ —NO₂ —H —H —OCF₃ —C(H)— —C(H)— 830 (IIa) or (IIb) —CH₃ —NO₂ —H —H—OCF₃ —C(H)— —N— 831 (IIa) or (IIb) —CH₃ —NO₂ —H —H —OCF₃ —N— —C(H)— 832(IIa) or (IIb) —CH₃ —NO₂ —H —H —F —C(H)— —C(H)— 833 (IIa) or (IIb) —CH₃—NO₂ —H —H —F —C(H)— —N— 834 (IIa) or (IIb) —CH₃ —NO₂ —H —H —F —N——C(H)— 835 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —H —C(H)— —C(H)— 836 (IIa)or (IIb) —CH₃ —NO₂ —H —CH₃ —H —C(H)— —N— 837 (IIa) or (IIb) —CH₃ —NO₂ —H—CH₃ —H —N— —C(H)— 838 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —CH₃ —C(H)——C(H)— 839 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —CH₃ —C(H)— —N— 840 (IIa) or(IIb) —CH₃ —NO₂ —H —CH₃ —CH₃ —N— —C(H)— 841 (IIa) or (IIb) —CH₃ —NO₂ —H—CH₃ —OCH₃ —C(H)— —C(H)— 842 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —OCH₃—C(H)— —N— 843 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —OCH₃ —N— —C(H)— 844(IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —OCF₃ —C(H)— —C(H)— 845 (IIa) or (IIb)—CH₃ —NO₂ —H —CH₃ —OCF₃ —C(H)— —N— 846 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃—OCF₃ —N— —C(H)— 847 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —F —C(H)— —C(H)—848 (IIa) or (IIb) —CH₃ —NO₂ —H —CH₃ —F —C(H)— —N— 849 (IIa) or (IIb)—CH₃ —NO₂ —H —CH₃ —F —N— —C(H)— 850 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —H—C(H)— —C(H)— 851 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —H —C(H)— —N— 852(IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —H —N— —C(H)— 853 (IIa) or (IIb) —CH₃—NO₂ —H —OCH₃ —CH₃ —C(H)— —C(H)— 854 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃—CH₃ —C(H)— —N— 855 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —CH₃ —N— —C(H)—856 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —OCH₃ —C(H)— —C(H)— 857 (IIa) or(IIb) —CH₃ —NO₂ —H —OCH₃ —OCH₃ —C(H)— —N— 858 (IIa) or (IIb) —CH₃ —NO₂—H —OCH₃ —OCH₃ —N— —C(H)— 859 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —OCF₃—C(H)— —C(H)— 860 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —OCF₃ —C(H)— —N— 861(IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —OCF₃ —N— —C(H)— 862 (IIa) or (IIb)—CH₃ —NO₂ —H —OCH₃ —F —C(H)— —C(H)— 863 (IIa) or (IIb) —CH₃ —NO₂ —H—OCH₃ —F —C(H)— —N— 864 (IIa) or (IIb) —CH₃ —NO₂ —H —OCH₃ —F —N— —C(H)—865 (IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —H —C(H)— —C(H)— 866 (IIa) or (IIb)—CH₃ —NO₂ —H —NO₂ —H —C(H)— —N— 867 (IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —H—N— —C(H)— 868 (IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —CH₃ —C(H)— —C(H)— 869(IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —CH₃ —C(H)— —N— 870 (IIa) or (IIb) —CH₃—NO₂ —H —NO₂ —CH₃ —N— —C(H)— 871 (IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —OCH₃—C(H)— —C(H)— 872 (IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —OCH₃ —C(H)— —N— 873(IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —OCH₃ —N— —C(H)— 874 (IIa) or (IIb)—CH₃ —NO₂ —H —NO₂ —OCF₃ —C(H)— —C(H)— 875 (IIa) or (IIb) —CH₃ —NO₂ —H—NO₂ —OCF₃ —C(H)— —N— 876 (IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —OCF₃ —N——C(H)— 877 (IIa) or (IIb) —CH₃ —NO₂ —H —NO₂ —F —C(H)— —C(H)— 878 (IIa)or (IIb) —CH₃ —NO₂ —H —NO₂ —F —C(H)— —N— 879 (IIa) or (IIb) —CH₃ —NO₂ —H—NO₂ —F —N— —C(H)— 880 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —H —C(H)— —C(H)—881 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —H —C(H)— —N— 882 (IIa) or (IIb)—CH₃ —NO₂ —CH₃ —H —H —N— —C(H)— 883 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H—CH₃ —C(H)— —C(H)— 884 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —CH₃ —C(H)— —N—885 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —CH₃ —N— —C(H)— 886 (IIa) or (IIb)—CH₃ —NO₂ —CH₃ —H —OCH₃ —C(H)— —C(H)— 887 (IIa) or (IIb) —CH₃ —NO₂ —CH₃—H —OCH₃ —C(H)— —N— 888 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —OCH₃ —N——C(H)— 889 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —OCF₃ —C(H)— —C(H)— 890(IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —OCF₃ —C(H)— —N— 891 (IIa) or (IIb)—CH₃ —NO₂ —CH₃ —H —OCF₃ —N— —C(H)— 892 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H—F —C(H)— —C(H)— 893 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —F —C(H)— —N— 894(IIa) or (IIb) —CH₃ —NO₂ —CH₃ —H —F —N— —C(H)— 895 (IIa) or (IIb) —CH₃—NO₂ —CH₃ —CH₃ —H —C(H)— —C(H)— 896 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —CH₃—H —C(H)— —N— 897 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —H —N— —C(H)— 898(IIa) or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —CH₃ —C(H)— —C(H)— 899 (IIa) or (IIb)—CH₃ —NO₂ —CH₃ —CH₃ —CH₃ —C(H)— —N— 900 (IIa) or (IIb) —CH₃ —NO₂ —CH₃—CH₃ —CH₃ —N— —C(H)— 901 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —OCH₃ —C(H)——C(H)— 902 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —OCH₃ —C(H)— —N— 903 (IIa)or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —OCH₃ —N— —C(H)— 904 (IIa) or (IIb) —CH₃—NO₂ —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 905 (IIa) or (IIb) —CH₃ —NO₂ —CH₃—CH₃ —OCF₃ —C(H)— —N— 906 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —OCF₃ —N——C(H)— 907 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —F —C(H)— —C(H)— 908 (IIa)or (IIb) —CH₃ —NO₂ —CH₃ —CH₃ —F —C(H)— —N— 909 (IIa) or (IIb) —CH₃ —NO₂—CH₃ —CH₃ —F —N— —C(H)— 910 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —H—C(H)— —C(H)— 911 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —H —C(H)— —N— 912(IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —H —N— —C(H)— 913 (IIa) or (IIb)—CH₃ —NO₂ —CH₃ —OCH₃ —CH₃ —C(H)— —C(H)— 914 (IIa) or (IIb) —CH₃ —NO₂—CH₃ —OCH₃ —CH₃ —C(H)— —N— 915 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —CH₃—N— —C(H)— 916 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —OCH₃ —C(H)— —C(H)—917 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —OCH₃ —C(H)— —N— 918 (IIa) or(IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —OCH₃ —N— —C(H)— 919 (IIa) or (IIb) —CH₃ —NO₂—CH₃ —OCH₃ —OCF₃ —C(H)— —C(H)— 920 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃—OCF₃ —C(H)— —N— 921 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —OCF₃ —N——C(H)— 922 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —F —C(H)— —C(H)— 923(IIa) or (IIb) —CH₃ —NO₂ —CH₃ —OCH₃ —F —C(H)— —N— 924 (IIa) or (IIb)—CH₃ —NO₂ —CH₃ —OCH₃ —F —N— —C(H)— 925 (IIa) or (IIb) —CH₃ —NO₂ —CH₃—NO₂ —H —C(H)— —C(H)— 926 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —H —C(H)——N— 927 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —H —N— —C(H)— 928 (IIa) or(IIb) —CH₃ —NO₂ —CH₃ —NO₂ —CH₃ —C(H)— —C(H)— 929 (IIa) or (IIb) —CH₃—NO₂ —CH₃ —NO₂ —CH₃ —C(H)— —N— 930 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —NO₂—CH₃ —N— —C(H)— 931 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —OCH₃ —C(H)——C(H)— 932 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —OCH₃ —C(H)— —N— 933 (IIa)or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —OCH₃ —N— —C(H)— 934 (IIa) or (IIb) —CH₃—NO₂ —CH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 935 (IIa) or (IIb) —CH₃ —NO₂ —CH₃—NO₂ —OCF₃ —C(H)— —N— 936 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —OCF₃ —N——C(H)— 937 (IIa) or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —F —C(H)— —C(H)— 938 (IIa)or (IIb) —CH₃ —NO₂ —CH₃ —NO₂ —F —C(H)— —N— 939 (IIa) or (IIb) —CH₃ —NO₂—CH₃ —NO₂ —F —N— —C(H)— 940 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —H —C(H)——C(H)— 941 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —H —C(H)— —N— 942 (IIa) or(IIb) —CH₃ —NO₂ —OCH₃ —H —H —N— —C(H)— 943 (IIa) or (IIb) —CH₃ —NO₂—OCH₃ —H —CH₃ —C(H)— —C(H)— 944 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —CH₃—C(H)— —N— 945 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —CH₃ —N— —C(H)— 946(IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —OCH₃ —C(H)— —C(H)— 947 (IIa) or (IIb)—CH₃ —NO₂ —OCH₃ —H —OCH₃ —C(H)— —N— 948 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃—H —OCH₃ —N— —C(H)— 949 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —OCF₃ —C(H)——C(H)— 950 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —OCF₃ —C(H)— —N— 951 (IIa)or (IIb) —CH₃ —NO₂ —OCH₃ —H —OCF₃ —N— —C(H)— 952 (IIa) or (IIb) —CH₃—NO₂ —OCH₃ —H —F —C(H)— —C(H)— 953 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —F—C(H)— —N— 954 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —H —F —N— —C(H)— 955 (IIa)or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —H —C(H)— —C(H)— 956 (IIa) or (IIb) —CH₃—NO₂ —OCH₃ —CH₃ —H —C(H)— —N— 957 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —H—N— —C(H)— 958 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —CH₃ —C(H)— —C(H)—959 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —CH₃ —C(H)— —N— 960 (IIa) or(IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —CH₃ —N— —C(H)— 961 (IIa) or (IIb) —CH₃ —NO₂—OCH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 962 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃—OCH₃ —C(H)— —N— 963 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —OCH₃ —N——C(H)— 964 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 965(IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —OCF₃ —C(H)— —N— 966 (IIa) or (IIb)—CH₃ —NO₂ —OCH₃ —CH₃ —OCF₃ —N— —C(H)— 967 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃—CH₃ —F —C(H)— —C(H)— 968 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —F —C(H)——N— 969 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —CH₃ —F —N— —C(H)— 970 (IIa) or(IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —H —C(H)— —C(H)— 971 (IIa) or (IIb) —CH₃—NO₂ —OCH₃ —OCH₃ —H —C(H)— —N— 972 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃—H —N— —C(H)— 973 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —CH₃ —C(H)——C(H)— 974 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —CH₃ —C(H)— —N— 975(IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —CH₃ —N— —C(H)— 976 (IIa) or (IIb)—CH₃ —NO₂ —OCH₃ —OCH₃ —OCH₃ —C(H)— —C(H)— 977 (IIa) or (IIb) —CH₃ —NO₂—OCH₃ —OCH₃ —OCH₃ —C(H)— —N— 978 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃—OCH₃ —N— —C(H)— 979 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —OCF₃ —C(H)——C(H)— 980 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —OCF₃ —C(H)— —N— 981(IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —OCF₃ —N— —C(H)— 982 (IIa) or (IIb)—CH₃ —NO₂ —OCH₃ —OCH₃ —F —C(H)— —C(H)— 983 (IIa) or (IIb) —CH₃ —NO₂—OCH₃ —OCH₃ —F —C(H)— —N— 984 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —OCH₃ —F—N— —C(H)— 985 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —H —C(H)— —C(H)— 986(IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —H —C(H)— —N— 987 (IIa) or (IIb)—CH₃ —NO₂ —OCH₃ —NO₂ —H —N— —C(H)— 988 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃—NO₂ —CH₃ —C(H)— —C(H)— 989 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —CH₃—C(H)— —N— 990 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —CH₃ —N— —C(H)— 991(IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —OCH₃ —C(H)— —C(H)— 992 (IIa) or(IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —OCH₃ —C(H)— —N— 993 (IIa) or (IIb) —CH₃ —NO₂—OCH₃ —NO₂ —OCH₃ —N— —C(H)— 994 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂—OCF₃ —C(H)— —C(H)— 995 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —OCF₃ —C(H)——N— 996 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —OCF₃ —N— —C(H)— 997 (IIa)or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —F —C(H)— —C(H)— 998 (IIa) or (IIb) —CH₃—NO₂ —OCH₃ —NO₂ —F —C(H)— —N— 999 (IIa) or (IIb) —CH₃ —NO₂ —OCH₃ —NO₂ —F—N— —C(H)— 1000 (IIa) or (IIb) —CH₃ —OCH₃ —H —H —H —C(H)— —C(H)— 1001(IIa) or (IIb) —CH₃ —OCH₃ —H —H —H —C(H)— —N— 1002 (IIa) or (IIb) —CH₃—OCH₃ —H —H —H —N— —C(H)— 1003 (IIa) or (IIb) —CH₃ —OCH₃ —H —H —CH₃—C(H)— —C(H)— 1004 (IIa) or (IIb) —CH₃ —OCH₃ —H —H —CH₃ —C(H)— —N— 1005(IIa) or (IIb) —CH₃ —OCH₃ —H —H —CH₃ —N— —C(H)— 1006 (IIa) or (IIb) —CH₃—OCH₃ —H —H —OCH₃ —C(H)— —C(H)— 1007 (IIa) or (IIb) —CH₃ —OCH₃ —H —H—OCH₃ —C(H)— —N— 1008 (IIa) or (IIb) —CH₃ —OCH₃ —H —H —OCH₃ —N— —C(H)—1009 (IIa) or (IIb) —CH₃ —OCH₃ —H —H —OCF₃ —C(H)— —C(H)— 1010 (IIa) or(IIb) —CH₃ —OCH₃ —H —H —OCF₃ —C(H)— —N— 1011 (IIa) or (IIb) —CH₃ —OCH₃—H —H —OCF₃ —N— —C(H)— 1012 (IIa) or (IIb) —CH₃ —OCH₃ —H —H —F —C(H)——C(H)— 1013 (IIa) or (IIb) —CH₃ —OCH₃ —H —H —F —C(H)— —N— 1014 (IIa) or(IIb) —CH₃ —OCH₃ —H —H —F —N— —C(H)— 1015 (IIa) or (IIb) —CH₃ —OCH₃ —H—CH₃ —H —C(H)— —C(H)— 1016 (IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —H —C(H)——N— 1017 (IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —H —N— —C(H)— 1018 (IIa) or(IIb) —CH₃ —OCH₃ —H —CH₃ —CH₃ —C(H)— —C(H)— 1019 (IIa) or (IIb) —CH₃—OCH₃ —H —CH₃ —CH₃ —C(H)— —N— 1020 (IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃—CH₃ —N— —C(H)— 1021 (IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —OCH₃ —C(H)——C(H)— 1022 (IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —OCH₃ —C(H)— —N— 1023(IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —OCH₃ —N— —C(H)— 1024 (IIa) or (IIb)—CH₃ —OCH₃ —H —CH₃ —OCF₃ —C(H)— —C(H)— 1025 (IIa) or (IIb) —CH₃ —OCH₃ —H—CH₃ —OCF₃ —C(H)— —N— 1026 (IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —OCF₃ —N——C(H)— 1027 (IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —F —C(H)— —C(H)— 1028(IIa) or (IIb) —CH₃ —OCH₃ —H —CH₃ —F —C(H)— —N— 1029 (IIa) or (IIb) —CH₃—OCH₃ —H —CH₃ —F —N— —C(H)— 1030 (IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —H—C(H)— —C(H)— 1031 (IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —H —C(H)— —N— 1032(IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —H —N— —C(H)— 1033 (IIa) or (IIb)—CH₃ —OCH₃ —H —OCH₃ —CH₃ —C(H)— —C(H)— 1034 (IIa) or (IIb) —CH₃ —OCH₃ —H—OCH₃ —CH₃ —C(H)— —N— 1035 (IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —CH₃ —N——C(H)— 1036 (IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —OCH₃ —C(H)— —C(H)— 1037(IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —OCH₃ —C(H)— —N— 1038 (IIa) or (IIb)—CH₃ —OCH₃ —H —OCH₃ —OCH₃ —N— —C(H)— 1039 (IIa) or (IIb) —CH₃ —OCH₃ —H—OCH₃ —OCF₃ —C(H)— —C(H)— 1040 (IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —OCF₃—C(H)— —N— 1041 (IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —OCF₃ —N— —C(H)— 1042(IIa) or (IIb) —CH₃ —OCH₃ —H —OCH₃ —F —C(H)— —C(H)— 1043 (IIa) or (IIb)—CH₃ —OCH₃ —H —OCH₃ —F —C(H)— —N— 1044 (IIa) or (IIb) —CH₃ —OCH₃ —H—OCH₃ —F —N— —C(H)— 1045 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —H —C(H)——C(H)— 1046 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —H —C(H)— —N— 1047 (IIa)or (IIb) —CH₃ —OCH₃ —H —NO₂ —H —N— —C(H)— 1048 (IIa) or (IIb) —CH₃ —OCH₃—H —NO₂ —CH₃ —C(H)— —C(H)— 1049 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —CH₃—C(H)— —N— 1050 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —CH₃ —N— —C(H)— 1051(IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —OCH₃ —C(H)— —C(H)— 1052 (IIa) or(IIb) —CH₃ —OCH₃ —H —NO₂ —OCH₃ —C(H)— —N— 1053 (IIa) or (IIb) —CH₃ —OCH₃—H —NO₂ —OCH₃ —N— —C(H)— 1054 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —OCF₃—C(H)— —C(H)— 1055 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —OCF₃ —C(H)— —N—1056 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —OCF₃ —N— —C(H)— 1057 (IIa) or(IIb) —CH₃ —OCH₃ —H —NO₂ —F —C(H)— —C(H)— 1058 (IIa) or (IIb) —CH₃ —OCH₃—H —NO₂ —F —C(H)— —N— 1059 (IIa) or (IIb) —CH₃ —OCH₃ —H —NO₂ —F —N——C(H)— 1060 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —H —C(H)— —C(H)— 1061(IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —H —C(H)— —N— 1062 (IIa) or (IIb) —CH₃—OCH₃ —CH₃ —H —H —N— —C(H)— 1063 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —CH₃—C(H)— —C(H)— 1064 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —CH₃ —C(H)— —N—1065 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —CH₃ —N— —C(H)— 1066 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —H —OCH₃ —C(H)— —C(H)— 1067 (IIa) or (IIb) —CH₃—OCH₃ —CH₃ —H —OCH₃ —C(H)— —N— 1068 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H—OCH₃ —N— —C(H)— 1069 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —OCF₃ —C(H)——C(H)— 1070 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —OCF₃ —C(H)— —N— 1071(IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —OCF₃ —N— —C(H)— 1072 (IIa) or (IIb)—CH₃ —OCH₃ —CH₃ —H —F —C(H)— —C(H)— 1073 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃—H —F —C(H)— —N— 1074 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —H —F —N— —C(H)—1075 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —H —C(H)— —C(H)— 1076 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —H —C(H)— —N— 1077 (IIa) or (IIb) —CH₃ —OCH₃—CH₃ —CH₃ —H —N— —C(H)— 1078 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —CH₃—C(H)— —C(H)— 1079 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —CH₃ —C(H)— —N—1080 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —CH₃ —N— —C(H)— 1081 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 1082 (IIa) or (IIb) —CH₃—OCH₃ —CH₃ —CH₃ —OCH₃ —C(H)— —N— 1083 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃—CH₃ —OCH₃ —N— —C(H)— 1084 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —OCF₃—C(H)— —C(H)— 1085 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —OCF₃ —C(H)— —N—1086 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —OCF₃ —N— —C(H)— 1087 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —CH₃ —F —C(H)— —C(H)— 1088 (IIa) or (IIb) —CH₃—OCH₃ —CH₃ —CH₃ —F —C(H)— —N— 1089 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —CH₃—F —N— —C(H)— 1090 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —H —C(H)— —C(H)—1091 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —H —C(H)— —N— 1092 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —H —N— —C(H)— 1093 (IIa) or (IIb) —CH₃ —OCH₃—CH₃ —OCH₃ —CH₃ —C(H)— —C(H)— 1094 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃—CH₃ —C(H)— —N— 1095 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —CH₃ —N——C(H)— 1096 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —OCH₃ —C(H)— —C(H)—1097 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —OCH₃ —C(H)— —N— 1098 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —OCH₃ —N— —C(H)— 1099 (IIa) or (IIb) —CH₃—OCH₃ —CH₃ —OCH₃ —OCF₃ —C(H)— —C(H)— 1100 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃—OCH₃ —OCF₃ —C(H)— —N— 1101 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —OCF₃—N— —C(H)— 1102 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —F —C(H)— —C(H)—1103 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —F —C(H)— —N— 1104 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —OCH₃ —F —N— —C(H)— 1105 (IIa) or (IIb) —CH₃ —OCH₃—CH₃ —NO₂ —H —C(H)— —C(H)— 1106 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —H—C(H)— —N— 1107 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —H —N— —C(H)— 1108(IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —CH₃ —C(H)— —C(H)— 1109 (IIa) or(IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —CH₃ —C(H)— —N— 1110 (IIa) or (IIb) —CH₃—OCH₃ —CH₃ —NO₂ —CH₃ —N— —C(H)— 1111 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂—OCH₃ —C(H)— —C(H)— 1112 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —OCH₃—C(H)— —N— 1113 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —OCH₃ —N— —C(H)—1114 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 1115 (IIa)or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —OCF₃ —C(H)— —N— 1116 (IIa) or (IIb) —CH₃—OCH₃ —CH₃ —NO₂ —OCF₃ —N— —C(H)— 1117 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃—NO₂ —F —C(H)— —C(H)— 1118 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —F —C(H)——N— 1119 (IIa) or (IIb) —CH₃ —OCH₃ —CH₃ —NO₂ —F —N— —C(H)— 1120 (IIa) or(IIb) —CH₃ —OCH₃ —OCH₃ —H —H —C(H)— —C(H)— 1121 (IIa) or (IIb) —CH₃—OCH₃ —OCH₃ —H —H —C(H)— —N— 1122 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —H—N— —C(H)— 1123 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —CH₃ —C(H)— —C(H)—1124 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —CH₃ —C(H)— —N— 1125 (IIa) or(IIb) —CH₃ —OCH₃ —OCH₃ —H —CH₃ —N— —C(H)— 1126 (IIa) or (IIb) —CH₃ —OCH₃—OCH₃ —H —OCH₃ —C(H)— —C(H)— 1127 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H—OCH₃ —C(H)— —N— 1128 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —OCH₃ —N——C(H)— 1129 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —OCF₃ —C(H)— —C(H)— 1130(IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —OCF₃ —C(H)— —N— 1131 (IIa) or (IIb)—CH₃ —OCH₃ —OCH₃ —H —OCF₃ —N— —C(H)— 1132 (IIa) or (IIb) —CH₃ —OCH₃—OCH₃ —H —F —C(H)— —C(H)— 1133 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —F—C(H)— —N— 1134 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —H —F —N— —C(H)— 1135(IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —H —C(H)— —C(H)— 1136 (IIa) or(IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —H —C(H)— —N— 1137 (IIa) or (IIb) —CH₃ —OCH₃—OCH₃ —CH₃ —H —N— —C(H)— 1138 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —CH₃—C(H)— —C(H)— 1139 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —CH₃ —C(H)— —N—1140 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —CH₃ —N— —C(H)— 1141 (IIa) or(IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 1142 (IIa) or (IIb) —CH₃—OCH₃ —OCH₃ —CH₃ —OCH₃ —C(H)— —N— 1143 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃—CH₃ —OCH₃ —N— —C(H)— 1144 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —OCF₃—C(H)— —C(H)— 1145 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —OCF₃ —C(H)— —N—1146 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —OCF₃ —N— —C(H)— 1147 (IIa) or(IIb) —CH₃ —OCH₃ —OCH₃ —CH₃ —F —C(H)— —C(H)— 1148 (IIa) or (IIb) —CH₃—OCH₃ —OCH₃ —CH₃ —F —C(H)— —N— 1149 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —CH₃—F —N— —C(H)— 1150 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —H —C(H)——C(H)— 1151 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —H —C(H)— —N— 1152(IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —H —N— —C(H)— 1153 (IIa) or (IIb)—CH₃ —OCH₃ —OCH₃ —OCH₃ —CH₃ —C(H)— —C(H)— 1154 (IIa) or (IIb) —CH₃ —OCH₃—OCH₃ —OCH₃ —CH₃ —C(H)— —N— 1155 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃—CH₃ —N— —C(H)— 1156 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —OCH₃ —C(H)——C(H)— 1157 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —OCH₃ —C(H)— —N— 1158(IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —OCH₃ —N— —C(H)— 1159 (IIa) or(IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —OCF₃ —C(H)— —C(H)— 1160 (IIa) or (IIb)—CH₃ —OCH₃ —OCH₃ —OCH₃ —OCF₃ —C(H)— —N— 1161 (IIa) or (IIb) —CH₃ —OCH₃—OCH₃ —OCH₃ —OCF₃ —N— —C(H)— 1162 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃—F —C(H)— —C(H)— 1163 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —F —C(H)——N— 1164 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —OCH₃ —F —N— —C(H)— 1165 (IIa)or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —H —C(H)— —C(H)— 1166 (IIa) or (IIb) —CH₃—OCH₃ —OCH₃ —NO₂ —H —C(H)— —N— 1167 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂—H —N— —C(H)— 1168 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —CH₃ —C(H)——C(H)— 1169 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —CH₃ —C(H)— —N— 1170(IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —CH₃ —N— —C(H)— 1171 (IIa) or (IIb)—CH₃ —OCH₃ —OCH₃ —NO₂ —OCH₃ —C(H)— —C(H)— 1172 (IIa) or (IIb) —CH₃ —OCH₃—OCH₃ —NO₂ —OCH₃ —C(H)— —N— 1173 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂—OCH₃ —N— —C(H)— 1174 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —OCF₃ —C(H)——C(H)— 1175 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —OCF₃ —C(H)— —N— 1176(IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —OCF₃ —N— —C(H)— 1177 (IIa) or(IIb) —CH₃ —OCH₃ —OCH₃ —NO₂ —F —C(H)— —C(H)— 1178 (IIa) or (IIb) —CH₃—OCH₃ —OCH₃ —NO₂ —F —C(H)— —N— 1179 (IIa) or (IIb) —CH₃ —OCH₃ —OCH₃ —NO₂—F —N— —C(H)— 1180 (IIa) or (IIb) —CH₂OH —H —H —H —H —C(H)— —C(H)— 1181(IIa) or (IIb) —CH₂OH —H —H —H —H —C(H)— —N— 1182 (IIa) or (IIb) —CH₂OH—H —H —H —H —N— —C(H)— 1183 (IIa) or (IIb) —CH₂OH —H —H —H —CH₃ —C(H)——C(H)— 1184 (IIa) or (IIb) —CH₂OH —H —H —H —CH₃ —C(H)— —N— 1185 (IIa) or(IIb) —CH₂OH —H —H —H —CH₃ —N— —C(H)— 1186 (IIa) or (IIb) —CH₂OH —H —H—H —OCH₃ —C(H)— —C(H)— 1187 (IIa) or (IIb) —CH₂OH —H —H —H —OCH₃ —C(H)——N— 1188 (IIa) or (IIb) —CH₂OH —H —H —H —OCH₃ —N— —C(H)— 1189 (IIa) or(IIb) —CH₂OH —H —H —H —OCF₃ —C(H)— —C(H)— 1190 (IIa) or (IIb) —CH₂OH —H—H —H —OCF₃ —C(H)— —N— 1191 (IIa) or (IIb) —CH₂OH —H —H —H —OCF₃ —N——C(H)— 1192 (IIa) or (IIb) —CH₂OH —H —H —H —F —C(H)— —C(H)— 1193 (IIa)or (IIb) —CH₂OH —H —H —H —F —C(H)— —N— 1194 (IIa) or (IIb) —CH₂OH —H —H—H —F —N— —C(H)— 1195 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —H —C(H)— —C(H)—1196 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —H —C(H)— —N— 1197 (IIa) or (IIb)—CH₂OH —H —H —CH₃ —H —N— —C(H)— 1198 (IIa) or (IIb) —CH₂OH —H —H —CH₃—CH₃ —C(H)— —C(H)— 1199 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —CH₃ —C(H)— —N—1200 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —CH₃ —N— —C(H)— 1201 (IIa) or(IIb) —CH₂OH —H —H —CH₃ —OCH₃ —C(H)— —C(H)— 1202 (IIa) or (IIb) —CH₂OH—H —H —CH₃ —OCH₃ —C(H)— —N— 1203 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —OCH₃—N— —C(H)— 1204 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —OCF₃ —C(H)— —C(H)—1205 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —OCF₃ —C(H)— —N— 1206 (IIa) or(IIb) —CH₂OH —H —H —CH₃ —OCF₃ —N— —C(H)— 1207 (IIa) or (IIb) —CH₂OH —H—H —CH₃ —F —C(H)— —C(H)— 1208 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —F —C(H)——N— 1209 (IIa) or (IIb) —CH₂OH —H —H —CH₃ —F —N— —C(H)— 1210 (IIa) or(IIb) —CH₂OH —H —H —OCH₃ —H —C(H)— —C(H)— 1211 (IIa) or (IIb) —CH₂OH —H—H —OCH₃ —H —C(H)— —N— 1212 (IIa) or (IIb) —CH₂OH —H —H —OCH₃ —H —N——C(H)— 1213 (IIa) or (IIb) —CH₂OH —H —H —OCH₃ —CH₃ —C(H)— —C(H)— 1214(IIa) or (IIb) —CH₂OH —H —H —OCH₃ —CH₃ —C(H)— —N— 1215 (IIa) or (IIb)—CH₂OH —H —H —OCH₃ —CH₃ —N— —C(H)— 1216 (IIa) or (IIb) —CH₂OH —H —H—OCH₃ —OCH₃ —C(H)— —C(H)— 1217 (IIa) or (IIb) —CH₂OH —H —H —OCH₃ —OCH₃—C(H)— —N— 1218 (IIa) or (IIb) —CH₂OH —H —H —OCH₃ —OCH₃ —N— —C(H)— 1219(IIa) or (IIb) —CH₂OH —H —H —OCH₃ —OCF₃ —C(H)— —C(H)— 1220 (IIa) or(IIb) —CH₂OH —H —H —OCH₃ —OCF₃ —C(H)— —N— 1221 (IIa) or (IIb) —CH₂OH —H—H —OCH₃ —OCF₃ —N— —C(H)— 1222 (IIa) or (IIb) —CH₂OH —H —H —OCH₃ —F—C(H)— —C(H)— 1223 (IIa) or (IIb) —CH₂OH —H —H —OCH₃ —F —C(H)— —N— 1224(IIa) or (IIb) —CH₂OH —H —H —OCH₃ —F —N— —C(H)— 1225 (IIa) or (IIb)—CH₂OH —H —H —NO₂ —H —C(H)— —C(H)— 1226 (IIa) or (IIb) —CH₂OH —H —H —NO₂—H —C(H)— —N— 1227 (IIa) or (IIb) —CH₂OH —H —H —NO₂ —H —N— —C(H)— 1228(IIa) or (IIb) —CH₂OH —H —H —NO₂ —CH₃ —C(H)— —C(H)— 1229 (IIa) or (IIb)—CH₂OH —H —H —NO₂ —CH₃ —C(H)— —N— 1230 (IIa) or (IIb) —CH₂OH —H —H —NO₂—CH₃ —N— —C(H)— 1231 (IIa) or (IIb) —CH₂OH —H —H —NO₂ —OCH₃ —C(H)——C(H)— 1232 (IIa) or (IIb) —CH₂OH —H —H —NO₂ —OCH₃ —C(H)— —N— 1233 (IIa)or (IIb) —CH₂OH —H —H —NO₂ —OCH₃ —N— —C(H)— 1234 (IIa) or (IIb) —CH₂OH—H —H —NO₂ —OCF₃ —C(H)— —C(H)— 1235 (IIa) or (IIb) —CH₂OH —H —H —NO₂—OCF₃ —C(H)— —N— 1236 (IIa) or (IIb) —CH₂OH —H —H —NO₂ —OCF₃ —N— —C(H)—1237 (IIa) or (IIb) —CH₂OH —H —H —NO₂ —F —C(H)— —C(H)— 1238 (IIa) or(IIb) —CH₂OH —H —H —NO₂ —F —C(H)— —N— 1239 (IIa) or (IIb) —CH₂OH —H —H—NO₂ —F —N— —C(H)— 1240 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —H —C(H)——C(H)— 1241 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —H —C(H)— —N— 1242 (IIa) or(IIb) —CH₂OH —H —CH₃ —H —H —N— —C(H)— 1243 (IIa) or (IIb) —CH₂OH —H —CH₃—H —CH₃ —C(H)— —C(H)— 1244 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —CH₃ —C(H)——N— 1245 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —CH₃ —N— —C(H)— 1246 (IIa) or(IIb) —CH₂OH —H —CH₃ —H —OCH₃ —C(H)— —C(H)— 1247 (IIa) or (IIb) —CH₂OH—H —CH₃ —H —OCH₃ —C(H)— —N— 1248 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —OCH₃—N— —C(H)— 1249 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —OCF₃ —C(H)— —C(H)—1250 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —OCF₃ —C(H)— —N— 1251 (IIa) or(IIb) —CH₂OH —H —CH₃ —H —OCF₃ —N— —C(H)— 1252 (IIa) or (IIb) —CH₂OH —H—CH₃ —H —F —C(H)— —C(H)— 1253 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —F —C(H)——N— 1254 (IIa) or (IIb) —CH₂OH —H —CH₃ —H —F —N— —C(H)— 1255 (IIa) or(IIb) —CH₂OH —H —CH₃ —CH₃ —H —C(H)— —C(H)— 1256 (IIa) or (IIb) —CH₂OH —H—CH₃ —CH₃ —H —C(H)— —N— 1257 (IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —H —N——C(H)— 1258 (IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —CH₃ —C(H)— —C(H)— 1259(IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —CH₃ —C(H)— —N— 1260 (IIa) or (IIb)—CH₂OH —H —CH₃ —CH₃ —CH₃ —N— —C(H)— 1261 (IIa) or (IIb) —CH₂OH —H —CH₃—CH₃ —OCH₃ —C(H)— —C(H)— 1262 (IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —OCH₃—C(H)— —N— 1263 (IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —OCH₃ —N— —C(H)— 1264(IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 1265 (IIa) or(IIb) —CH₂OH —H —CH₃ —CH₃ —OCF₃ —C(H)— —N— 1266 (IIa) or (IIb) —CH₂OH —H—CH₃ —CH₃ —OCF₃ —N— —C(H)— 1267 (IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —F—C(H)— —C(H)— 1268 (IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —F —C(H)— —N— 1269(IIa) or (IIb) —CH₂OH —H —CH₃ —CH₃ —F —N— —C(H)— 1270 (IIa) or (IIb)—CH₂OH —H —CH₃ —OCH₃ —H —C(H)— —C(H)— 1271 (IIa) or (IIb) —CH₂OH —H —CH₃—OCH₃ —H —C(H)— —N— 1272 (IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —H —N——C(H)— 1273 (IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —CH₃ —C(H)— —C(H)— 1274(IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —CH₃ —C(H)— —N— 1275 (IIa) or (IIb)—CH₂OH —H —CH₃ —OCH₃ —CH₃ —N— —C(H)— 1276 (IIa) or (IIb) —CH₂OH —H —CH₃—OCH₃ —OCH₃ —C(H)— —C(H)— 1277 (IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —OCH₃—C(H)— —N— 1278 (IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —OCH₃ —N— —C(H)—1279 (IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —OCF₃ —C(H)— —C(H)— 1280 (IIa)or (IIb) —CH₂OH —H —CH₃ —OCH₃ —OCF₃ —C(H)— —N— 1281 (IIa) or (IIb)—CH₂OH —H —CH₃ —OCH₃ —OCF₃ —N— —C(H)— 1282 (IIa) or (IIb) —CH₂OH —H —CH₃—OCH₃ —F —C(H)— —C(H)— 1283 (IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —F—C(H)— —N— 1284 (IIa) or (IIb) —CH₂OH —H —CH₃ —OCH₃ —F —N— —C(H)— 1285(IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —H —C(H)— —C(H)— 1286 (IIa) or (IIb)—CH₂OH —H —CH₃ —NO₂ —H —C(H)— —N— 1287 (IIa) or (IIb) —CH₂OH —H —CH₃—NO₂ —H —N— —C(H)— 1288 (IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —CH₃ —C(H)——C(H)— 1289 (IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —CH₃ —C(H)— —N— 1290(IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —CH₃ —N— —C(H)— 1291 (IIa) or (IIb)—CH₂OH —H —CH₃ —NO₂ —OCH₃ —C(H)— —C(H)— 1292 (IIa) or (IIb) —CH₂OH —H—CH₃ —NO₂ —OCH₃ —C(H)— —N— 1293 (IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —OCH₃—N— —C(H)— 1294 (IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —OCF₃ —C(H)— —C(H)—1295 (IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —OCF₃ —C(H)— —N— 1296 (IIa) or(IIb) —CH₂OH —H —CH₃ —NO₂ —OCF₃ —N— —C(H)— 1297 (IIa) or (IIb) —CH₂OH —H—CH₃ —NO₂ —F —C(H)— —C(H)— 1298 (IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —F—C(H)— —N— 1299 (IIa) or (IIb) —CH₂OH —H —CH₃ —NO₂ —F —N— —C(H)— 1300(IIa) or (IIb) —CH₂OH —H —OCH₃ —H —H —C(H)— —C(H)— 1301 (IIa) or (IIb)—CH₂OH —H —OCH₃ —H —H —C(H)— —N— 1302 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H—H —N— —C(H)— 1303 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H —CH₃ —C(H)— —C(H)—1304 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H —CH₃ —C(H)— —N— 1305 (IIa) or(IIb) —CH₂OH —H —OCH₃ —H —CH₃ —N— —C(H)— 1306 (IIa) or (IIb) —CH₂OH —H—OCH₃ —H —OCH₃ —C(H)— —C(H)— 1307 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H—OCH₃ —C(H)— —N— 1308 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H —OCH₃ —N— —C(H)—1309 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H —OCF₃ —C(H)— —C(H)— 1310 (IIa) or(IIb) —CH₂OH —H —OCH₃ —H —OCF₃ —C(H)— —N— 1311 (IIa) or (IIb) —CH₂OH —H—OCH₃ —H —OCF₃ —N— —C(H)— 1312 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H —F—C(H)— —C(H)— 1313 (IIa) or (IIb) —CH₂OH —H —OCH₃ —H —F —C(H)— —N— 1314(IIa) or (IIb) —CH₂OH —H —OCH₃ —H —F —N— —C(H)— 1315 (IIa) or (IIb)—CH₂OH —H —OCH₃ —CH₃ —H —C(H)— —C(H)— 1316 (IIa) or (IIb) —CH₂OH —H—OCH₃ —CH₃ —H —C(H)— —N— 1317 (IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —H —N——C(H)— 1318 (IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —CH₃ —C(H)— —C(H)— 1319(IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —CH₃ —C(H)— —N— 1320 (IIa) or (IIb)—CH₂OH —H —OCH₃ —CH₃ —CH₃ —N— —C(H)— 1321 (IIa) or (IIb) —CH₂OH —H —OCH₃—CH₃ —OCH₃ —C(H)— —C(H)— 1322 (IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —OCH₃—C(H)— —N— 1323 (IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —OCH₃ —N— —C(H)—1324 (IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 1325 (IIa)or (IIb) —CH₂OH —H —OCH₃ —CH₃ —OCF₃ —C(H)— —N— 1326 (IIa) or (IIb)—CH₂OH —H —OCH₃ —CH₃ —OCF₃ —N— —C(H)— 1327 (IIa) or (IIb) —CH₂OH —H—OCH₃ —CH₃ —F —C(H)— —C(H)— 1328 (IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —F—C(H)— —N— 1329 (IIa) or (IIb) —CH₂OH —H —OCH₃ —CH₃ —F —N— —C(H)— 1330(IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃ —H —C(H)— —C(H)— 1331 (IIa) or(IIb) —CH₂OH —H —OCH₃ —OCH₃ —H —C(H)— —N— 1332 (IIa) or (IIb) —CH₂OH —H—OCH₃ —OCH₃ —H —N— —C(H)— 1333 (IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃ —CH₃—C(H)— —C(H)— 1334 (IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃ —CH₃ —C(H)— —N—1335 (IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃ —CH₃ —N— —C(H)— 1336 (IIa) or(IIb) —CH₂OH —H —OCH₃ —OCH₃ —OCH₃ —C(H)— —C(H)— 1337 (IIa) or (IIb)—CH₂OH —H —OCH₃ —OCH₃ —OCH₃ —C(H)— —N— 1338 (IIa) or (IIb) —CH₂OH —H—OCH₃ —OCH₃ —OCH₃ —N— —C(H)— 1339 (IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃—OCF₃ —C(H)— —C(H)— 1340 (IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃ —OCF₃—C(H)— —N— 1341 (IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃ —OCF₃ —N— —C(H)—1342 (IIa) or (IIb) —CH₂OH —H —OCH₃ —OCH₃ —F —C(H)— —C(H)— 1343 (IIa) or(IIb) —CH₂OH —H —OCH₃ —OCH₃ —F —C(H)— —N— 1344 (IIa) or (IIb) —CH₂OH —H—OCH₃ —OCH₃ —F —N— —C(H)— 1345 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —H—C(H)— —C(H)— 1346 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —H —C(H)— —N—1347 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —H —N— —C(H)— 1348 (IIa) or(IIb) —CH₂OH —H —OCH₃ —NO₂ —CH₃ —C(H)— —C(H)— 1349 (IIa) or (IIb) —CH₂OH—H —OCH₃ —NO₂ —CH₃ —C(H)— —N— 1350 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂—CH₃ —N— —C(H)— 1351 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —OCH₃ —C(H)——C(H)— 1352 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —OCH₃ —C(H)— —N— 1353(IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —OCH₃ —N— —C(H)— 1354 (IIa) or (IIb)—CH₂OH —H —OCH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 1355 (IIa) or (IIb) —CH₂OH —H—OCH₃ —NO₂ —OCF₃ —C(H)— —N— 1356 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂—OCF₃ —N— —C(H)— 1357 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —F —C(H)——C(H)— 1358 (IIa) or (IIb) —CH₂OH —H —OCH₃ —NO₂ —F —C(H)— —N— 1359 (IIa)or (IIb) —CH₂OH —H —OCH₃ —NO₂ —F —N— —C(H)— 1360 (IIa) or (IIb) —CH₂OH—NO₂ —H —H —H —C(H)— —C(H)— 1361 (IIa) or (IIb) —CH₂OH —NO₂ —H —H —H—C(H)— —N— 1362 (IIa) or (IIb) —CH₂OH —NO₂ —H —H —H —N— —C(H)— 1363(IIa) or (IIb) —CH₂OH —NO₂ —H —H —CH₃ —C(H)— —C(H)— 1364 (IIa) or (IIb)—CH₂OH —NO₂ —H —H —CH₃ —C(H)— —N— 1365 (IIa) or (IIb) —CH₂OH —NO₂ —H —H—CH₃ —N— —C(H)— 1366 (IIa) or (IIb) —CH₂OH —NO₂ —H —H —OCH₃ —C(H)——C(H)— 1367 (IIa) or (IIb) —CH₂OH —NO₂ —H —H —OCH₃ —C(H)— —N— 1368 (IIa)or (IIb) —CH₂OH —NO₂ —H —H —OCH₃ —N— —C(H)— 1369 (IIa) or (IIb) —CH₂OH—NO₂ —H —H —OCF₃ —C(H)— —C(H)— 1370 (IIa) or (IIb) —CH₂OH —NO₂ —H —H—OCF₃ —C(H)— —N— 1371 (IIa) or (IIb) —CH₂OH —NO₂ —H —H —OCF₃ —N— —C(H)—1372 (IIa) or (IIb) —CH₂OH —NO₂ —H —H —F —C(H)— —C(H)— 1373 (IIa) or(IIb) —CH₂OH —NO₂ —H —H —F —C(H)— —N— 1374 (IIa) or (IIb) —CH₂OH —NO₂ —H—H —F —N— —C(H)— 1375 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃ —H —C(H)——C(H)— 1376 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃ —H —C(H)— —N— 1377 (IIa)or (IIb) —CH₂OH —NO₂ —H —CH₃ —H —N— —C(H)— 1378 (IIa) or (IIb) —CH₂OH—NO₂ —H —CH₃ —CH₃ —C(H)— —C(H)— 1379 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃—CH₃ —C(H)— —N— 1380 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃ —CH₃ —N— —C(H)—1381 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃ —OCH₃ —C(H)— —C(H)— 1382 (IIa)or (IIb) —CH₂OH —NO₂ —H —CH₃ —OCH₃ —C(H)— —N— 1383 (IIa) or (IIb) —CH₂OH—NO₂ —H —CH₃ —OCH₃ —N— —C(H)— 1384 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃—OCF₃ —C(H)— —C(H)— 1385 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃ —OCF₃ —C(H)——N— 1386 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃ —OCF₃ —N— —C(H)— 1387 (IIa)or (IIb) —CH₂OH —NO₂ —H —CH₃ —F —C(H)— —C(H)— 1388 (IIa) or (IIb) —CH₂OH—NO₂ —H —CH₃ —F —C(H)— —N— 1389 (IIa) or (IIb) —CH₂OH —NO₂ —H —CH₃ —F—N— —C(H)— 1390 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃ —H —C(H)— —C(H)—1391 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃ —H —C(H)— —N— 1392 (IIa) or(IIb) —CH₂OH —NO₂ —H —OCH₃ —H —N— —C(H)— 1393 (IIa) or (IIb) —CH₂OH —NO₂—H —OCH₃ —CH₃ —C(H)— —C(H)— 1394 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃—CH₃ —C(H)— —N— 1395 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃ —CH₃ —N— —C(H)—1396 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃ —OCH₃ —C(H)— —C(H)— 1397 (IIa)or (IIb) —CH₂OH —NO₂ —H —OCH₃ —OCH₃ —C(H)— —N— 1398 (IIa) or (IIb)—CH₂OH —NO₂ —H —OCH₃ —OCH₃ —N— —C(H)— 1399 (IIa) or (IIb) —CH₂OH —NO₂ —H—OCH₃ —OCF₃ —C(H)— —C(H)— 1400 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃ —OCF₃—C(H)— —N— 1401 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃ —OCF₃ —N— —C(H)—1402 (IIa) or (IIb) —CH₂OH —NO₂ —H —OCH₃ —F —C(H)— —C(H)— 1403 (IIa) or(IIb) —CH₂OH —NO₂ —H —OCH₃ —F —C(H)— —N— 1404 (IIa) or (IIb) —CH₂OH —NO₂—H —OCH₃ —F —N— —C(H)— 1405 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂ —H —C(H)——C(H)— 1406 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂ —H —C(H)— —N— 1407 (IIa)or (IIb) —CH₂OH —NO₂ —H —NO₂ —H —N— —C(H)— 1408 (IIa) or (IIb) —CH₂OH—NO₂ —H —NO₂ —CH₃ —C(H)— —C(H)— 1409 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂—CH₃ —C(H)— —N— 1410 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂ —CH₃ —N— —C(H)—1411 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂ —OCH₃ —C(H)— —C(H)— 1412 (IIa)or (IIb) —CH₂OH —NO₂ —H —NO₂ —OCH₃ —C(H)— —N— 1413 (IIa) or (IIb) —CH₂OH—NO₂ —H —NO₂ —OCH₃ —N— —C(H)— 1414 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂—OCF₃ —C(H)— —C(H)— 1415 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂ —OCF₃ —C(H)——N— 1416 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂ —OCF₃ —N— —C(H)— 1417 (IIa)or (IIb) —CH₂OH —NO₂ —H —NO₂ —F —C(H)— —C(H)— 1418 (IIa) or (IIb) —CH₂OH—NO₂ —H —NO₂ —F —C(H)— —N— 1419 (IIa) or (IIb) —CH₂OH —NO₂ —H —NO₂ —F—N— —C(H)— 1420 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —H —C(H)— —C(H)— 1421(IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —H —C(H)— —N— 1422 (IIa) or (IIb)—CH₂OH —NO₂ —CH₃ —H —H —N— —C(H)— 1423 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃—H —CH₃ —C(H)— —C(H)— 1424 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —CH₃—C(H)— —N— 1425 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —CH₃ —N— —C(H)— 1426(IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —OCH₃ —C(H)— —C(H)— 1427 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —H —OCH₃ —C(H)— —N— 1428 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —H —OCH₃ —N— —C(H)— 1429 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H—OCF₃ —C(H)— —C(H)— 1430 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —OCF₃ —C(H)——N— 1431 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —OCF₃ —N— —C(H)— 1432 (IIa)or (IIb) —CH₂OH —NO₂ —CH₃ —H —F —C(H)— —C(H)— 1433 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —H —F —C(H)— —N— 1434 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —H —F—N— —C(H)— 1435 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —H —C(H)— —C(H)—1436 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —H —C(H)— —N— 1437 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —H —N— —C(H)— 1438 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —CH₃ —CH₃ —C(H)— —C(H)— 1439 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃—CH₃ —CH₃ —C(H)— —N— 1440 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —CH₃ —N——C(H)— 1441 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —OCH₃ —C(H)— —C(H)—1442 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —OCH₃ —C(H)— —N— 1443 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —OCH₃ —N— —C(H)— 1444 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 1445 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃—CH₃ —OCF₃ —C(H)— —N— 1446 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —OCF₃—N— —C(H)— 1447 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —F —C(H)— —C(H)—1448 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —F —C(H)— —N— 1449 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —CH₃ —F —N— —C(H)— 1450 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —OCH₃ —H —C(H)— —C(H)— 1451 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃—OCH₃ —H —C(H)— —N— 1452 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —H —N——C(H)— 1453 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —CH₃ —C(H)— —C(H)—1454 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —CH₃ —C(H)— —N— 1455 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —CH₃ —N— —C(H)— 1456 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —OCH₃ —OCH₃ —C(H)— —C(H)— 1457 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃—OCH₃ —OCH₃ —C(H)— —N— 1458 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —OCH₃—N— —C(H)— 1459 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —OCF₃ —C(H)——C(H)— 1460 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —OCF₃ —C(H)— —N— 1461(IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —OCF₃ —N— —C(H)— 1462 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —OCH₃ —F —C(H)— —C(H)— 1463 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —OCH₃ —F —C(H)— —N— 1464 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —OCH₃—F —N— —C(H)— 1465 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —H —C(H)— —C(H)—1466 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —H —C(H)— —N— 1467 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —H —N— —C(H)— 1468 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —NO₂ —CH₃ —C(H)— —C(H)— 1469 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃—NO₂ —CH₃ —C(H)— —N— 1470 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —CH₃ —N——C(H)— 1471 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —OCH₃ —C(H)— —C(H)—1472 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —OCH₃ —C(H)— —N— 1473 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —OCH₃ —N— —C(H)— 1474 (IIa) or (IIb) —CH₂OH—NO₂ —CH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 1475 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃—NO₂ —OCF₃ —C(H)— —N— 1476 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —OCF₃—N— —C(H)— 1477 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —F —C(H)— —C(H)—1478 (IIa) or (IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —F —C(H)— —N— 1479 (IIa) or(IIb) —CH₂OH —NO₂ —CH₃ —NO₂ —F —N— —C(H)— 1480 (IIa) or (IIb) —CH₂OH—NO₂ —OCH₃ —H —H —C(H)— —C(H)— 1481 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H—H —C(H)— —N— 1482 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H —H —N— —C(H)—1483 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H —CH₃ —C(H)— —C(H)— 1484 (IIa)or (IIb) —CH₂OH —NO₂ —OCH₃ —H —CH₃ —C(H)— —N— 1485 (IIa) or (IIb) —CH₂OH—NO₂ —OCH₃ —H —CH₃ —N— —C(H)— 1486 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H—OCH₃ —C(H)— —C(H)— 1487 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H —OCH₃—C(H)— —N— 1488 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H —OCH₃ —N— —C(H)—1489 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H —OCF₃ —C(H)— —C(H)— 1490 (IIa)or (IIb) —CH₂OH —NO₂ —OCH₃ —H —OCF₃ —C(H)— —N— 1491 (IIa) or (IIb)—CH₂OH —NO₂ —OCH₃ —H —OCF₃ —N— —C(H)— 1492 (IIa) or (IIb) —CH₂OH —NO₂—OCH₃ —H —F —C(H)— —C(H)— 1493 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H —F—C(H)— —N— 1494 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —H —F —N— —C(H)— 1495(IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —H —C(H)— —C(H)— 1496 (IIa) or(IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —H —C(H)— —N— 1497 (IIa) or (IIb) —CH₂OH—NO₂ —OCH₃ —CH₃ —H —N— —C(H)— 1498 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃—CH₃ —C(H)— —C(H)— 1499 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —CH₃—C(H)— —N— 1500 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —CH₃ —N— —C(H)—1501 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —OCH₃ —C(H)— —C(H)— 1502(IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —OCH₃ —C(H)— —N— 1503 (IIa) or(IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —OCH₃ —N— —C(H)— 1504 (IIa) or (IIb) —CH₂OH—NO₂ —OCH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 1505 (IIa) or (IIb) —CH₂OH —NO₂—OCH₃ —CH₃ —OCF₃ —C(H)— —N— 1506 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃—OCF₃ —N— —C(H)— 1507 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —F —C(H)——C(H)— 1508 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —F —C(H)— —N— 1509(IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —CH₃ —F —N— —C(H)— 1510 (IIa) or (IIb)—CH₂OH —NO₂ —OCH₃ —OCH₃ —H —C(H)— —C(H)— 1511 (IIa) or (IIb) —CH₂OH —NO₂—OCH₃ —OCH₃ —H —C(H)— —N— 1512 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —H—N— —C(H)— 1513 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —CH₃ —C(H)——C(H)— 1514 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —CH₃ —C(H)— —N— 1515(IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —CH₃ —N— —C(H)— 1516 (IIa) or(IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —OCH₃ —C(H)— —C(H)— 1517 (IIa) or (IIb)—CH₂OH —NO₂ —OCH₃ —OCH₃ —OCH₃ —C(H)— —N— 1518 (IIa) or (IIb) —CH₂OH —NO₂—OCH₃ —OCH₃ —OCH₃ —N— —C(H)— 1519 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃—OCF₃ —C(H)— —C(H)— 1520 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —OCF₃—C(H)— —N— 1521 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —OCF₃ —N— —C(H)—1522 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —F —C(H)— —C(H)— 1523 (IIa)or (IIb) —CH₂OH —NO₂ —OCH₃ —OCH₃ —F —C(H)— —N— 1524 (IIa) or (IIb)—CH₂OH —NO₂ —OCH₃ —OCH₃ —F —N— —C(H)— 1525 (IIa) or (IIb) —CH₂OH —NO₂—OCH₃ —NO₂ —H —C(H)— —C(H)— 1526 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂—H —C(H)— —N— 1527 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —H —N— —C(H)—1528 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —CH₃ —C(H)— —C(H)— 1529 (IIa)or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —CH₃ —C(H)— —N— 1530 (IIa) or (IIb)—CH₂OH —NO₂ —OCH₃ —NO₂ —CH₃ —N— —C(H)— 1531 (IIa) or (IIb) —CH₂OH —NO₂—OCH₃ —NO₂ —OCH₃ —C(H)— —C(H)— 1532 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃—NO₂ —OCH₃ —C(H)— —N— 1533 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —OCH₃—N— —C(H)— 1534 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —OCF₃ —C(H)——C(H)— 1535 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —OCF₃ —C(H)— —N— 1536(IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —OCF₃ —N— —C(H)— 1537 (IIa) or(IIb) —CH₂OH —NO₂ —OCH₃ —NO₂ —F —C(H)— —C(H)— 1538 (IIa) or (IIb) —CH₂OH—NO₂ —OCH₃ —NO₂ —F —C(H)— —N— 1539 (IIa) or (IIb) —CH₂OH —NO₂ —OCH₃ —NO₂—F —N— —C(H)— 1540 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H —H —C(H)— —C(H)—1541 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H —H —C(H)— —N— 1542 (IIa) or (IIb)—CH₂OH —OCH₃ —H —H —H —N— —C(H)— 1543 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H—CH₃ —C(H)— —C(H)— 1544 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H —CH₃ —C(H)——N— 1545 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H —CH₃ —N— —C(H)— 1546 (IIa) or(IIb) —CH₂OH —OCH₃ —H —H —OCH₃ —C(H)— —C(H)— 1547 (IIa) or (IIb) —CH₂OH—OCH₃ —H —H —OCH₃ —C(H)— —N— 1548 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H—OCH₃ —N— —C(H)— 1549 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H —OCF₃ —C(H)——C(H)— 1550 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H —OCF₃ —C(H)— —N— 1551(IIa) or (IIb) —CH₂OH —OCH₃ —H —H —OCF₃ —N— —C(H)— 1552 (IIa) or (IIb)—CH₂OH —OCH₃ —H —H —F —C(H)— —C(H)— 1553 (IIa) or (IIb) —CH₂OH —OCH₃ —H—H —F —C(H)— —N— 1554 (IIa) or (IIb) —CH₂OH —OCH₃ —H —H —F —N— —C(H)—1555 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃ —H —C(H)— —C(H)— 1556 (IIa) or(IIb) —CH₂OH —OCH₃ —H —CH₃ —H —C(H)— —N— 1557 (IIa) or (IIb) —CH₂OH—OCH₃ —H —CH₃ —H —N— —C(H)— 1558 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃—CH₃ —C(H)— —C(H)— 1559 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃ —CH₃ —C(H)——N— 1560 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃ —CH₃ —N— —C(H)— 1561 (IIa)or (IIb) —CH₂OH —OCH₃ —H —CH₃ —OCH₃ —C(H)— —C(H)— 1562 (IIa) or (IIb)—CH₂OH —OCH₃ —H —CH₃ —OCH₃ —C(H)— —N— 1563 (IIa) or (IIb) —CH₂OH —OCH₃—H —CH₃ —OCH₃ —N— —C(H)— 1564 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃ —OCF₃—C(H)— —C(H)— 1565 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃ —OCF₃ —C(H)— —N—1566 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃ —OCF₃ —N— —C(H)— 1567 (IIa) or(IIb) —CH₂OH —OCH₃ —H —CH₃ —F —C(H)— —C(H)— 1568 (IIa) or (IIb) —CH₂OH—OCH₃ —H —CH₃ —F —C(H)— —N— 1569 (IIa) or (IIb) —CH₂OH —OCH₃ —H —CH₃ —F—N— —C(H)— 1570 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —H —C(H)— —C(H)—1571 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —H —C(H)— —N— 1572 (IIa) or(IIb) —CH₂OH —OCH₃ —H —OCH₃ —H —N— —C(H)— 1573 (IIa) or (IIb) —CH₂OH—OCH₃ —H —OCH₃ —CH₃ —C(H)— —C(H)— 1574 (IIa) or (IIb) —CH₂OH —OCH₃ —H—OCH₃ —CH₃ —C(H)— —N— 1575 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —CH₃ —N——C(H)— 1576 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —OCH₃ —C(H)— —C(H)—1577 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —OCH₃ —C(H)— —N— 1578 (IIa) or(IIb) —CH₂OH —OCH₃ —H —OCH₃ —OCH₃ —N— —C(H)— 1579 (IIa) or (IIb) —CH₂OH—OCH₃ —H —OCH₃ —OCF₃ —C(H)— —C(H)— 1580 (IIa) or (IIb) —CH₂OH —OCH₃ —H—OCH₃ —OCF₃ —C(H)— —N— 1581 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —OCF₃—N— —C(H)— 1582 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —F —C(H)— —C(H)—1583 (IIa) or (IIb) —CH₂OH —OCH₃ —H —OCH₃ —F —C(H)— —N— 1584 (IIa) or(IIb) —CH₂OH —OCH₃ —H —OCH₃ —F —N— —C(H)— 1585 (IIa) or (IIb) —CH₂OH—OCH₃ —H —NO₂ —H —C(H)— —C(H)— 1586 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂—H —C(H)— —N— 1587 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂ —H —N— —C(H)—1588 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂ —CH₃ —C(H)— —C(H)— 1589 (IIa)or (IIb) —CH₂OH —OCH₃ —H —NO₂ —CH₃ —C(H)— —N— 1590 (IIa) or (IIb) —CH₂OH—OCH₃ —H —NO₂ —CH₃ —N— —C(H)— 1591 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂—OCH₃ —C(H)— —C(H)— 1592 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂ —OCH₃—C(H)— —N— 1593 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂ —OCH₃ —N— —C(H)—1594 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂ —OCF₃ —C(H)— —C(H)— 1595 (IIa)or (IIb) —CH₂OH —OCH₃ —H —NO₂ —OCF₃ —C(H)— —N— 1596 (IIa) or (IIb)—CH₂OH —OCH₃ —H —NO₂ —OCF₃ —N— —C(H)— 1597 (IIa) or (IIb) —CH₂OH —OCH₃—H —NO₂ —F —C(H)— —C(H)— 1598 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂ —F—C(H)— —N— 1599 (IIa) or (IIb) —CH₂OH —OCH₃ —H —NO₂ —F —N— —C(H)— 1600(IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —H —C(H)— —C(H)— 1601 (IIa) or (IIb)—CH₂OH —OCH₃ —CH₃ —H —H —C(H)— —N— 1602 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃—H —H —N— —C(H)— 1603 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —CH₃ —C(H)——C(H)— 1604 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —CH₃ —C(H)— —N— 1605(IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —CH₃ —N— —C(H)— 1606 (IIa) or (IIb)—CH₂OH —OCH₃ —CH₃ —H —OCH₃ —C(H)— —C(H)— 1607 (IIa) or (IIb) —CH₂OH—OCH₃ —CH₃ —H —OCH₃ —C(H)— —N— 1608 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H—OCH₃ —N— —C(H)— 1609 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —OCF₃ —C(H)——C(H)— 1610 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —OCF₃ —C(H)— —N— 1611(IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —OCF₃ —N— —C(H)— 1612 (IIa) or (IIb)—CH₂OH —OCH₃ —CH₃ —H —F —C(H)— —C(H)— 1613 (IIa) or (IIb) —CH₂OH —OCH₃—CH₃ —H —F —C(H)— —N— 1614 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —H —F —N——C(H)— 1615 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —H —C(H)— —C(H)— 1616(IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —H —C(H)— —N— 1617 (IIa) or (IIb)—CH₂OH —OCH₃ —CH₃ —CH₃ —H —N— —C(H)— 1618 (IIa) or (IIb) —CH₂OH —OCH₃—CH₃ —CH₃ —CH₃ —C(H)— —C(H)— 1619 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃—CH₃ —C(H)— —N— 1620 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —CH₃ —N——C(H)— 1621 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —OCH₃ —C(H)— —C(H)—1622 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —OCH₃ —C(H)— —N— 1623 (IIa)or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —OCH₃ —N— —C(H)— 1624 (IIa) or (IIb)—CH₂OH —OCH₃ —CH₃ —CH₃ —OCF₃ —C(H)— —C(H)— 1625 (IIa) or (IIb) —CH₂OH—OCH₃ —CH₃ —CH₃ —OCF₃ —C(H)— —N— 1626 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃—CH₃ —OCF₃ —N— —C(H)— 1627 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —F—C(H)— —C(H)— 1628 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —F —C(H)— —N—1629 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —CH₃ —F —N— —C(H)— 1630 (IIa) or(IIb) —CH₂OH —OCH₃ —CH₃ —OCH₃ —H —C(H)— —C(H)— 1631 (IIa) or (IIb)—CH₂OH —OCH₃ —CH₃ —OCH₃ —H —C(H)— —N— 1632 (IIa) or (IIb) —CH₂OH —OCH₃—CH₃ —OCH₃ —H —N— —C(H)— 1633 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —OCH₃—CH₃ —C(H)— —C(H)— 1634 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —OCH₃ —CH₃—C(H)— —N— 1635 (IIa) or (IIb) —CH₂OH —OCH₃ —CH₃ —OCH₃ —CH₃ —N— —C(H)—1700 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —OCH₃ —OCF₃ —C(H)— —N— 1701 (IIa)or (IIb) —CH₂OH —OCH₃ —OCH₃ —OCH₃ —OCF₃ —N— —C(H)— 1702 (IIa) or (IIb)—CH₂OH —OCH₃ —OCH₃ —OCH₃ —F —C(H)— —C(H)— 1703 (IIa) or (IIb) —CH₂OH—OCH₃ —OCH₃ —OCH₃ —F —C(H)— —N— 1704 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃—OCH₃ —F —N— —C(H)— 1705 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —H—C(H)— —C(H)— 1706 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —H —C(H)— —N—1707 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —H —N— —C(H)— 1708 (IIa) or(IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —CH₃ —C(H)— —C(H)— 1709 (IIa) or (IIb)—CH₂OH —OCH₃ —OCH₃ —NO₂ —CH₃ —C(H)— —N— 1710 (IIa) or (IIb) —CH₂OH —OCH₃—OCH₃ —NO₂ —CH₃ —N— —C(H)— 1711 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂—OCH₃ —C(H)— —C(H)— 1712 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —OCH₃—C(H)— —N— 1713 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —OCH₃ —N— —C(H)—1714 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —OCF₃ —C(H)— —C(H)— 1715(IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —OCF₃ —C(H)— —N— 1716 (IIa) or(IIb) —CH₂OH —OCH₃ —OCH₃ —NO₂ —OCF₃ —N— —C(H)— 1717 (IIa) or (IIb)—CH₂OH —OCH₃ —OCH₃ —NO₂ —F —C(H)— —C(H)— 1718 (IIa) or (IIb) —CH₂OH—OCH₃ —OCH₃ —NO₂ —F —C(H)— —N— 1719 (IIa) or (IIb) —CH₂OH —OCH₃ —OCH₃—NO₂ —F —N— —C(H)—

[0297] The following are additional embodiments in connection with eachof the Compounds 100(IIa) through 1719(IIa) or 1719(IIb), above: thecompound has a —CH₃ at a position para to the 6-membered ring's point ofattachment to the triple bond; the compound has a —CF₃ at a positionpara to the 6-membered ring's point of attachment to the triple bond;the compound has a —F at a position para to the 6-membered ring's pointof attachment to the triple bond; the compound has a —Cl at a positionpara to the 6-membered ring's point of attachment to the triple bond;the compound has a —NO₂ at a position para to the 6-membered ring'spoint of attachment to the triple bond; the compound has a —C(O)CH₃ at aposition para to the 6-membered ring's point of attachment to the triplebond; the compound has a —C(CH₃)₃ at a position para to the 6-memberedring's point of attachment to the triple bond; the compound has a—CH(CH₃)₂ at a position para to the 6-membered ring's point ofattachment to the triple bond; the compound has a —OC(O)CH₃ at aposition para to the 6-membered ring's point of attachment to the triplebond; the compound has a —H at a position meta to the 6-membered ring'spoint of attachment to the triple bond; the compound has a —CH₃ at aposition meta to the 6-membered ring's point of attachment to the triplebond; the compound has a —CF₃ at a position meta to the 6-memberedring's point of attachment to the triple bond; the compound has a —F ata position meta to the 6-membered ring's point of attachment to thetriple bond; the compound has a —Cl at a position meta to the 6-memberedring's point of attachment to the triple bond; the compound has a —NO₂at a position meta to the 6-membered ring's point of attachment to thetriple bond; the compound has a —C(O)CH₃ at a position meta to the6-membered ring's point of attachment to the triple bond; the compoundhas a —C(CH₃)₃ at a position meta to the 6-membered ring's point ofattachment to the triple bond; the compound has a —CH(CH₃)₂ at aposition meta to the 6-membered ring's point of attachment to the triplebond; the compound has a —OC(O)CH₃ at a position meta to the 6-memberedring's point of attachment to the triple bond; the compound has a —H ata position ortho to the 6-membered ring's point of attachment to thetriple bond; the compound has a —CH₃ at a position ortho to the6-membered ring's point of attachment to the triple bond; the compoundhas a —CF₃ at a position ortho to the 6-membered ring's point ofattachment to the triple bond; the compound has a —F at a position orthoto the 6-membered ring's point of attachment to the triple bond; thecompound has a —Cl at a position ortho to the 6-membered ring's point ofattachment to the triple bond; the compound has a —NO₂ at a positionortho to the 6-membered ring's point of attachment to the triple bond;the compound has a —C(O)CH₃ at a position ortho to the 6-membered ring'spoint of attachment to the triple bond; the compound has a —C(CH₃)₃ at aposition ortho to the 6-membered ring's point of attachment to thetriple bond; the compound has a —CH(CH₃)₂ at a position ortho to the6-membered ring's point of attachment to the triple bond; and thecompound has a —OC(O)CH₃ at a position ortho to the 6-membered ring'spoint of attachment to the triple bond.

5.3 Definitions

[0298] As used herein, the terms used above having following meaning:

[0299] “—(C₁-C₁₀)alkyl” means a saturated straight chain or branchednon-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representativesaturated straight chain —(C₁-C₁₀)alkyls include -methyl, -ethyl,-n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl,and -n-decyl. Representative saturated branched —(C₁-C₁₀)alkyls include-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl,-2-methylbutyl, -3-methylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl,-2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2-methylhexyl,-3-methylhexyl, -4-methylhexyl, -5-methylhexyl, -2,3-dimethylbutyl,-2,3-dimethylpentyl, -2,4-dimethylpentyl, -2,3-dimethylhexyl,-2,4-dimethylhexyl, -2,5-dimethylhexyl, -2,2-dimethylpentyl,-2,2-dimethylhexyl, -3,3-dimethylpentyl, -3,3-dimethylhexyl,-4,4-dimethylhexyl, -2-ethylpentyl, -3-ethylpentyl, -2-ethylhexyl,-3-ethylhexyl, -4-ethylhexyl, -2-methyl-2-ethylpentyl,-2-methyl-3-ethylpentyl, -2-methyl-4-ethylpentyl,-2-methyl-2-ethylhexyl, -2-methyl-3-ethylhexyl, -2-methyl -4-ethylhexyl,-2,2-diethylpentyl, -3,3-diethylhexyl, -2,2-diethylhexyl,-3,3-diethylhexyl and the like.

[0300] “—(C₁-C₆)alkyl” means a saturated straight chain or branchednon-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representativesaturated straight chain —(C₁-C₆)alkyls include -methyl, -ethyl,-n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative saturatedbranched —(C₁-C₆)alkyls include -isopropyl, -sec-butyl, -isobutyl,-tert-butyl, -isopentyl, -2-methylbutyl, -3-methylbutyl,-2,2-dimethylbutyl, -2,3-dimethylbutyl, -2-methylpentyl,-3-methylpentyl, -4-methylpentyl and the like.

[0301] “—(C₁-C₄)alkyl” means a saturated straight chain or branchednon-cyclic hydrocarbon having from 1 to 4 carbon atoms. Representativesaturated straight chain —(C₁-C₄)alkyls include -methyl, -ethyl,-n-propyl, and -n-butyl. Representative saturated branched—(C₁-C₄)alkyls include -isopropyl, -sec-butyl, -isobutyl, and-tert-butyl.

[0302] “—(C₁-C₃)alkyl” means a saturated straight chain or branchednon-cyclic hydrocarbon having from 1 to 3 carbon atoms. Representativesaturated straight chain —(C₁-C₃)alkyls include -methyl, -ethyl, and-n-propyl. A representative saturated branched —(C₁-C₃)alkyl is-isopropyl.

[0303] “—(C₂-C₁₀)alkenyl” means a straight chain or branched nonfrom 2to 10 carbon atoms and including at least one carbon-carbon double bond.Representative straight chain and branched (C₂-C₁₀)alkyl-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl,-3-decenyl and the like.

[0304] “—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl and the like.

[0305] “—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at lease onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.

[0306] “—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at lease onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl and the like.

[0307] “—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon havingfrom 3 to 10 carbon atoms. Representative (C₃-C₁₀)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl,-cyclooctyl, -cyclononyl, and -cyclodecyl.

[0308] “—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon havingfrom 3 to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

[0309] “—(C₈-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring systemhaving from 8 to 14 carbon atoms and at least one saturated cyclic alkylring. Representative —(C₈-C₁₄)bicycloalkyls include -indanyl,-1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl,-perhydronaphthyl and the like.

[0310] “—(C₈-C₁₄)tricycloalkyl” means a tri-cyclic hydrocarbon ringsystem having from 8 to 14 carbon atoms and at least one saturated ring.Representative —(C₈-C₁₄)tricycloalkyls include -pyrenyl,-1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl, -aceanthreneyl,-1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl,-perhydrophenanthrenyl and the like.

[0311] “—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbonhaving at least one carbon-carbon double bond in the cyclic system andfrom 5 to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl,-cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl,-cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl,-cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and thelike.

[0312] “—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbonhaving at least one carbon-carbon double bond in the cyclic system andfrom 5 to 8 carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.

[0313] “—(C₈-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ringsystem having at least one carbon-carbon double bond in each ring andfrom 8 to 14 carbon atoms. Representative —(C₈-C₁₄)bicycloalkenylsinclude -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl,-1,2,7,8-tetrahydronaphthalenyl and the like.

[0314] “—(C₈-C₁₄)tricycloalkenyl” means a tri-cyclic hydrocarbon ringsystem having at least one carbon-carbon double bond in each ring andfrom 8 to 14 carbon atoms. Representative —(C₈-C₁₄)tricycloalkenylsinclude -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,-as-indacenyl, -s-indacenyl and the like.

[0315] “-(5- to 10-membered)heteroaryl” means an aromatic heterocyclering of 5 to 10 members, including both mono- and bicyclic ring systems,where at least one carbon atom of one or both of the rings is replacedwith a heteroatom independently selected from nitrogen, oxygen, andsulfur. One or both of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. Representative (5- to10-membered)heteroaryls include pyridyl, furyl, benzofuranyl,thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl,benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl and thelike.

[0316] “-(3- to 7-membered)heterocycle” or “-(3- to7-membered)heterocyclo” means a 3- to 7-membered monocyclic heterocyclicring which is either saturated, unsaturated, non-aromatic or aromatic. A3- or a 4-membered -(3- to 7-membered)heterocycle can contain up to 3heteroatoms, a 5-membered -(3- to 7-membered)heterocycle can contain upto 4 heteroatoms, a 6-membered -(3- to 7-membered)heterocycle cancontain up to 6 heteroatoms, and a 7-membered -(3- to7-membered)heterocycle can contain up to 7 heteroatoms. Each heteroatomis independently selected from nitrogen, which can be quatemized;oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to7-membered)heterocycle can be attached via any heteroatom or carbonatom. Representative -(3- to 7-membered)heterocycles include pyridyl,furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl andthe like.

[0317] “-(3- to 5-membered)heterocycle” or “-(3- to5-membered)heterocyclo” means a 3- to 5-membered monocyclic heterocyclicring which is either saturated, unsaturated, non-aromatic or aromatic. A3- or 4-membered -(3- to 5-membered)heterocycle can contain up to 3heteroatoms and a 5-membered -(3- to 5-membered)heterocycle can containup to 4 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quater4nized; oxygen; and sulfur, includingsulfoxide and sulfone. The -(3- to 5-membered)heterocycle can beattached via any heteroatom or carbon atom. Representative -(3- to5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl,pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydrothiophenyl and the like.

[0318] “-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring having a saturated, unsaturated, non-aromatic oraromatic group. A -(7- to 10-membered)bicycloheterocycle contains from 1to 4 heteroatoms independently selected from nitrogen, which can bequatemized; oxygen; and sulfur, including sulfoxide and sulfone. The (7-to 10-membered)bicycloheterocycle can be attached via any heteroatom orcarbon atom. Representative -(7- to 10-membered)bicycloheterocyclesinclude -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl,-indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl,-purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -carbazolyl, -β-carbolinyl, 1,3-benzodioxole and thelike.

[0319] “—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety suchas anthryl and phenanthryl.

[0320] “—CH₂(halo)” means a methyl group wherein one of the hydrogens ofthe methyl group has been replaced with a halogen. Representative—CH₂(halo) groups include —CH₂F, —CH₂Cl, —CH₂Br and —CH₂I.

[0321] “—CH(halo)₂” means a methyl group wherein two of the hydrogens ofthe methyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, CHBrCl, CHClI and—CHI₂.

[0322] “—C(halo)₃” means a methyl group wherein each of the hydrogens ofthe methyl group has been replaced with a halogen. Representative—C(halo)₃ groups include —CF₃, —CF₂Cl, —CCl₃, —CBr₃, —CFBr₂ and —CI₃.

[0323] “—Halogen” or “-halo” means —F, —Cl, —Br or —I.

[0324] The term “animal,” includes, but is not limited to, a cow,monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat,rabbit, guinea pig and human.

[0325] The phrase “pharmaceutically acceptable salt,” as used herein, isa salt formed from an acid and a basic nitrogen group of one of thePiperazine Compounds. Illustrative salts include, but are not limited,to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fuimarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also refers to a saltprepared from a Piperazine Compound having an acidic functional group,such as a carboxylic acid functional group, and a pharmaceuticallyacceptable inorganic or organic base. Suitable bases include, but arenot limited to, hydroxides of alkali metals such as sodium, potassium,and lithium; hydroxides of alkaline earth metal such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia and organic amines, such as unsubstituted or hydroxy-substitutedmono-, di- or trialkylamines; dicyclohexylamine; tributyl amine;pyridine; N-methyl—N-ethylamine; diethylamine-; triethylamine; mono-,bis- or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis- ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine ortris—(hydroxymethyl)methylamine, N,N-di-lower alkyl—N—(hydroxy loweralkyl)-amines, such as N,N-dimethyl—N-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine and the like.

[0326] The phrase “effective amount” when used in connection with aPiperazine Compound means an amount effective for: (a) treating orpreventing a Condition; or (b) inhibiting mGluR5 or mGluR1 function in acell.

[0327] The phrase “effective amount” when used in connection withanother therapeutic agent means an amount for providing the therapeuticeffect of the therapeutic agent.

[0328] When a first group is “substituted with one or more” secondgroups, each of one or more of the first group's hydrogen atoms isreplaced with a second group.

[0329] In one embodiment, a first group is substituted with up to threesecond groups.

[0330] In another embodiment, a first group is substituted with one ortwo second groups.

[0331] In another embodiment, a first group is substituted with only onesecond group.

[0332] The term “UI” means urinary incontinence.

[0333] The term “ALS” means amyotrophic lateral sclerosis.

[0334] The phrase “treatment of” and “treating” includes theamelioration or cessation a Condition or a symptom thereof

[0335] The phrase “prevention of” and “preventing” includes theavoidance of the onset of a Condition or a symptom thereof.

5.4 Methods for Making the Piperazine Compounds

[0336] The Piperazine Compounds can be made using conventional organicsyntheses and/or by the following illustrative methods.

[0337] Piperazine Compounds can be obtained by reacting a compound offormula A with an alkyl iodide, R₂I, at low temperature, e.g., about 0°C. to about −78° C., in the presence of lithium dilsopropylamide (“LDA”)in hexamethylphosphoramide (“HMPA”) as shown below in Scheme A:

[0338] A representative procedure for coupling a terminal acetylene withan alkyl iodide is provided in G. M. Strunz et al., Can. J. Chem.419-432 (1996).

[0339] Piperazine Compounds can also be obtained by reacting a compoundof formula A with an aryl iodide at room temperature in ethyl acetate inthe presence of Pd(Ph₃P)₂OAc₂, CuI, and Et₃N, as shown below in SchemeB:

[0340] A representative procedure for coupling a terminal acetylene withan aryl iodide is provided in L. A. Hay et al., J. Org. Chem. 5050-5058(1998).

[0341] The compound of formula A can be prepared by reacting a compoundof formula B with propynoic acid in the presence of1-hydroxybenzotriazolehydrate (“HOBT”) and 1,3-diisopropylcarbodiimide(“DIC”) as shown below in Scheme C:

[0342] A representative procedure for coupling a carboxylic acid with anamine is provided in F. M. Martin et al., Bioorg. Med. Chem. Lett.2887-2892 (1999).

[0343] The compound of formula A can also be prepared by reacting acompound of formula B with propynoyl chloride in the presence oftertiary amine, such as triethylamine, as shown below in Scheme D:

[0344] A representative procedure for coupling an acid chloride with anamine is provided in T. R. Herrin et al., J. Med. Chem. 1216-1223(1975).

[0345] The compound of formula B can be prepared by reacting a2-halo-substituted pyridine of formula C with piperazine D inchloroform, in the presence of triethylamine (TEA), at a temperature of50° C. as shown below in Scheme E:

[0346] wherein X is I, Br, Cl, or F.

[0347] A representative procedure for reacting a 2-halo-piperidine withpiperazine is provided in E. J. Jacobsen et al., J. Med. Chem. 1145-1151(1990).

[0348] The substituted 2-halo-pyridines C are commercially available orcan be prepared by methods well known to those skilled in the art.

[0349] Piperazine Compounds containing R₂ groups other than the R₂groups exemplified in Schemes A through D can be prepared usinganalogous methods.

[0350] Certain Piperazine Compounds may have asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. APiperazine Compound can be in the form of an optical isomer or adiastereomer. Accordingly, the invention encompasses PiperazineCompounds and their uses as described herein in the form of theiroptical isomers, diasteriomers and mixtures thereof, including a racemicmixture.

[0351] In addition, one or more hydrogen, carbon or other atoms of aPiperazine Compound can be replaced by an isotope of the hydrogen,carbon or other atoms. Such compounds, which are encompassed by thepresent invention, are useful as research and diagnostic tools inmetabolism pharmacokinetic studies and in binding assays.

5.5 Therapeutic Uses of the Piperazine Compounds

[0352] In accordance with the invention, the Piperazine Compounds areadministered to an animal in need of treatment or prevention of aCondition.

[0353] In one embodiment, an effective amount of a Piperazine Compoundcan be used to treat or prevent any condition treatable or preventableby inhibiting mGluR5. Examples of conditions that are treatable orpreventable by inhibiting mGluR5 include, but are not limited to, pain,an addictive disorder, Parkinson's disease, parkinsonism, anxiety, apruritic condition, and psychosis.

[0354] In another embodiment, an effective amount of a PiperazineCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting mGluR1. Examples of conditions that aretreatable or preventable by inhibiting mGluR1 include, but are notlimited to, pain, UI, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, a seizure, stroke, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia and depression.

[0355] The Piperazine Compounds can be used to treat or prevent acute orchronic pain. Examples of pain treatable or preventable using thePiperazine Compounds include, but are not limited to, cancer pain,central pain, labor pain, myocardial infarction pain, pancreatic pain,colic pain, post-operative pain, headache pain, muscle pain, painassociated with intensive care, arthritic pain, neuropathic pain, andpain associated with a periodontal disease, including gingivitis andperiodontitis.

[0356] The Piperazine Compounds can also be used for inhibiting,preventing, or treating pain associated with inflammation or with aninflammatory disease in an animal. The pain to be inhibited, treated orprevented may be associated with inflammation associated with aninflammatory disease, which can arise where there is an inflammation ofthe body tissue, and which can be a local inflammatory response and/or asystemic inflammation. For example, the Piperazine Compounds can be usedto inhibit, treat, or prevent pain associated with inflammatory diseasesincluding, but not limited to: organ transplant rejection; reoxygenationinjury resulting from organ transplantation (see Grupp et al., J. Mol.Cell Cardiol. 31:297-303 (1999)) including, but not limited to,transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory lung diseases, such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory diseases of the eye, including comeal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory diseases of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory diseases of the skin, includingsclerodermatitis, psoriasis and eczema; inflammatory diseases of thecentral nervous system, including chronic demyelinating diseases of thenervous system, multiple sclerosis, AIDS-related neurodegeneration andAlzheimer s disease, infectious meningitis, encephalomyelitis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosisand viral or autoimmune encephalitis; autoimmune diseases, includingType I and Type II diabetes mellitus; diabetic complications, including,but not limited to, diabetic cataract, glaucoma, retinopathy,nephropathy (such as microaluminuria and progressive diabeticnephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy,gangrene of the feet, atherosclerotic coronary arterial disease,peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma,foot ulcers, joint problems, and a skin or mucous membrane complication(such as an infection, a shin spot, a candidal infection or necrobiosislipoidica diabeticorum); immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory diseases of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andatherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. The PiperazineCompounds can also be used for inhibiting, treating, or preventing painassociated with inflammatory disease that can, for example, be asystemic inflammation of the body, exemplified by gram-positive or gramnegative shock, hemorrhagic or anaphylactic shock, or shock induced bycancer chemotherapy in response to pro-inflammatory cytokines, e.g.,shock associated with pro-inflammatory cytokines. Such shock can beinduced, e.g., by a chemotherapeutic agent that is adminstered as atreatment for cancer.

[0357] The Piperazine Compounds can be used to treat or prevent UI.Examples of UI treatable or preventable using the Piperazine Compoundsinclude, but are not limited to, urge incontinence, stress incontinence,overflow incontinence, neurogenic incontinence, and total incontinence.

[0358] The Piperazine Compounds can be used to treat or prevent anaddictive disorder, including but not limited to, an eating disorder, animpulse-control disorder, an alcohol-related disorder, anicotine-related disorder, an amphetamine-related disorder, acannabis-related disorder, a cocaine-related disorder, anhallucinogen-related disorder, an inhalant-related disorders, and anopioid-related disorder, all of which are further sub-classified aslisted below.

[0359] Eating disorders include, but are not limited to, BulimiaNervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; andEating Disorder not otherwise specified (NOS).

[0360] Impulse control disorders include, but are not limited to,Intermittent Explosive Disorder, Kleptomania, Pyromania, PathologicalGambling, Trichotillomania, and Impulse Control Disorder not otherwisespecified (NOS).

[0361] Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse,Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium,Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia,Alcohol-Induced Persisting Arnnestic Disorder, Alcohol Dependence,Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-InducedMood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced SexualDysfunction, Alcohol-Induced Sleep Disorder, Alcohol-Related Disordernot otherwise specified (NOS), Alcohol Intoxication, and AlcoholWithdrawal.

[0362] Nicotine-related disorders include, but are not limited to,Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related Disordernot otherwise specified (NOS).

[0363] Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium,Amphetamine-Induced Psychotic Disorder with delusions,Amphetamine-Induced Psychotic Disorders with hallucinations,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder, and Amphetamine Related Disorder not otherwise specified(NOS).

[0364] Cannabis-related disorders include, but are not limited to,Cannabis Dependence, Cannabis Abuse, Cannabis Intoxication, CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder withdelusions, Cannabis-Induced Psychotic Disorder with hallucinations,Cannabis-Induced Anxiety Disorder, and Cannabis Related Disorder nototherwise specified (NOS).

[0365] Cocaine-related disorders include, but are not limited to,Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, CocaineWithdrawal, Cocaine Intoxication Delirium, Cocaine-Induced PsychoticDisorder with delusions, Cocaine-Induced Psychotic Disorders withhallucinations, Cocaine-Induced Mood Disorder, Cocaine-Induced AnxietyDisorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced SleepDisorder, and Cocaine Related Disorder not otherwise specified (NOS).

[0366] Hallucinogen-related disorders include, but are not limited to,Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication,Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder with delusions,Hallucinogen-Induced Psychotic Disorders with hallucinations,Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced AnxietyDisorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-InducedSleep Disorder, Hallucinogen Persisting Perception Disorder(Flashbacks), and Hallucinogen Related Disorder not otherwise specified(NOS).

[0367] Inhalant-related disorders include, but are not limited to,Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, InhalantIntoxication Delirium, Inhalant-Induced Psychotic Disorder withdelusions, Inhalant-Induced Psychotic Disorder with hallucinations,Inhalant-Induced Anxiety Disorder, and Inhalant Related Disorder nototherwise specified (NOS).

[0368] Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Intoxication, Opioid IntoxicationDelirium, Opioid-Induced Psychotic Disorder with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, Opioid Withdrawal, and Opioid Related Disorder nototherwise specified (NOS).

[0369] The Piperazine Compounds can be used to treat or preventParkinson's disease and parkinsonism and the symptoms associated withParkinson's disease and parkinsonism, including but not limited to,bradykinesia, muscular rigidity, resting tremor, and impairment ofpostural balance.

[0370] The Piperazine Compounds can be used to treat or preventgeneralized anxiety or severe anxiety and the symptoms associated withanxiety, including but not limited to, restlessness, tension,tachycardia, dyspnea, depression including chronic “neurotic”depression, panic disorder, agoraphobia and other specific phobias,eating disorders, and personality disorders.

[0371] The Piperazine Compounds can be used to treat or preventepilepsy, including but not limited to, partial epilepsy, generalizedepilepsy, and the symptoms associated with epilepsy, including but notlimited to, simple partial seizures, jacksonian seizures, complexpartial (psychomotor) seizures, convulsive seizures (grand mal ortonic-clonic seizures), petit mal (absence) seizures, and statusepilepticus.

[0372] The Piperazine Compounds can be used to treat or prevent aseizure, including but not limited to, infantile spasms, febrileseizures, and epileptic seizures.

[0373] The Piperazine Compounds can be used to treat or prevent strokes,including but not limited to, ischemic strokes and hemorrhagic strokes.

[0374] The Piperazine Compounds can be used to treat or prevent apruritic condition, including but not limited to, pruritus caused by dryskin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritusvulvae et ani, malaria, insect bites, pediculosis, contact dermatitis,drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis,lichen planus, lichen simplex chronicus, exfoliative dermatitis,folliculitis, bullous pemphigoid, or fiberglass dermatitis.

[0375] The Piperazine Compounds can be used to treat or preventpsychosis, including but not limited to, schizophrenia, includingparanoid schizophrenia, hebephrenic or disorganized schizophrenia,catatonic schizophrenia, undifferentiated schizophrenia, negative ordeficit subtype schizophrenia, and non-deficit schizophrenia; adelusional disorder, including erotomanic subtype delusional disorder,grandiose subtype delusional disorder, jealous subtype delusionaldisorder, persecutory subtype delusional disorder, and somatic subtypedelusional disorder; and brief psychosis.

[0376] The Piperazine Compounds can be used to treat or prevent acognitive disorder, including but not limited to, delirium and dementiasuch as multi-infarct dementia, dementia pugilistica, dementia caused byAIDS, and dementia caused by Alzheimer's disease.

[0377] The Piperazine Compounds can be used to treat or prevent a memorydeficiency, including but not limited to, dissociative amnesia anddissociative fugue.

[0378] The Piperazine Compounds can be used to treat or preventrestricted brain function, including but not limited to, that caused bysurgery or an organ transplant, restricted blood supply to the brain, aspinal cord injury, a head injury, hypoxia, cardiac arrest, orhypoglycemia.

[0379] The Piperazine Compounds can be used to treat or preventHuntington's chorea.

[0380] The Piperazine Compounds can be used to treat or prevent ALS.

[0381] The Piperazine Compounds can be used to treat or preventretinopathy, including but not limited to, arteriosclerotic retinopathy,diabetic arteriosclerotic retinopathy, hypertensive retinopathy,non-proliferative retinopathy, and proliferative retinopathy.

[0382] The Piperazine Compounds can be used to treat or prevent a musclespasm.

[0383] The Piperazine Compounds can be used to treat or prevent amigraine.

[0384] The Piperazine Compounds can be used to treat or preventvomiting, including but not limited to, nausea vomiting, dry vomiting(retching), and regurgitation.

[0385] The Piperazine Compounds can be used to treat or preventdyskinesia, including but not limited to, tardive dyskinesia and biliarydyskinesia.

[0386] The Piperazine Compounds can be used to treat or preventdepression, including but not limited to, major depression and bipolardisorder.

[0387] Without wishing to be bound by theory, Applicants believe thatthe Piperazine Compounds are antagonists for mGluR5.

[0388] The invention also relates to methods for inhibiting mGluR5function in a cell comprising contacting a cell capable of expressingmGluR5 with an amount of a Piperazine Compound effective to inhibitmGluR5 function in the cell. This method can be used in vitro, forexample, as an assay to select cells that express mGluR5 and,accordingly, are useful as part of an assay to select compounds usefulfor treating or preventing pain, an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, a pruritic condition or psychosis. Themethod is also useful for inhibiting mGluR5 function in a cell in vivo,in an animal, a human in one embodiment, by contacting a cell, in ananimal, with an amount of a Piperazine Compound effective to inhibitmGluR5 function in the cell. In one embodiment, the method is useful fortreating or preventing pain in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing an addictivedisorder in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing Parkinson's disease in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing parkinsonism in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing anxiety inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing a pruritic condition in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing psychosis in an animal in need thereof. Examples of cellscapable of expressing mGluR5 are neuronal and glial cells of the centralnervous system, particularly the brain, especially in the nucleusaccumbens. Methods for assaying cells that express mGluR5 are well knownin the art.

[0389] Without wishing to be bound by theory, Applicants believe thatthe Piperazine Compounds are antagonists for mGluR1.

[0390] The invention also relates to methods for inhibiting mGluR1function in a cell comprising contacting a cell capable of expressingmGluR1 with an amount of a Piperazine Compound effective to inhibitmGluR1 function in the cell. This method can be used in vitro, forexample, as an assay to select cells that express mGluR1 and,accordingly, are useful as part of an assay to select compounds usefulfor treating or preventing pain, UI, an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, epilepsy, a seizure, stroke, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia or depression. The methodis also useful for inhibiting mGluR1 function in a cell in vivo, in ananimal, a human in one embodiment, by contacting a cell, in an animal,with an amount of a Piperazine Compound effective to inhibit mGluR1function in the cell. In one embodiment, the method is useful fortreating or preventing pain in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing UT in ananimal in need thereof. In another embodiment, the method is useful fortreating or preventing an addictive disorder in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing Parkinson's disease in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing parkinsonismin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing anxiety in an animal in need thereof.In another embodiment, the method is useful for treating or preventingepilepsy in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing a seizure in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing stroke in an animal in need thereof. In another embodiment,the method is useful for treating or preventing a pruritic condition inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing psychosis in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing acognitive disorder in an animal in need thereof. In another embodiment,the method is useful for treating or preventing a memory deficit in ananimal in need thereof. In another embodiment, the method is useful fortreating or preventing restricted brain function in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing Huntington's chorea in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing ALS in ananimal in need thereof. In another embodiment, the method is useful fortreating or preventing dementia in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing retinopathyin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing a muscle spasm in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing a migraine in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing vomiting inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing dyskinesia in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventingdepression in an animal in need thereof.

[0391] Examples of cells capable of expressing mGluR1 include, but arenot limited to, cerebellar Purkinje neuron cells, Purkinje cell bodies(punctate), cells of spine(s) of the cerebellum; neurons and neurophilcells of olfactory-bulb glomeruli; cells of the superficial layer of thecerebral cortex; hippocampus cells; thalamus cells; superior colliculuscells; and spinal trigeminal nucleus cells. Methods for assaying cellsthat express mGluR1 are well known in the art.

5.6 Therapeutic/Prophylactic Administration and Compositions of theInvention

[0392] Due to their activity, the Piperazine Compounds areadvantageously useful in veterinary and human medicine. As describedabove, the Piperazine Compounds are useful for treating or preventing aCondition in an animal in need thereof.

[0393] When administered to an animal, the Piperazine Compounds areadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The presentcompositions, which comprise a Piperazine Compound, can be administeredorally. The Piperazine Compounds of the invention can also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral, rectal, and intestinal mucosa, etc.) and can beadministered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the Piperazine Compound.

[0394] Methods of administration include, but are not limited to,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intracerebral, intravaginal,transderrnal, rectal, by inhalation, or topical, particularly to theears, nose, eyes, or skin. The mode of administration is left to thediscretion of the practitioner. In most instances, administration willresult in the release of the Piperazine Compounds into the bloodstream.

[0395] In specific embodiments, it can be desirable to administer thePiperazine Compounds locally. This can be achieved, for example, and notby way of limitation, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository orenema, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

[0396] In certain embodiments, it can be desirable to introduce thePiperazine Compounds into the central nervous system or gastrointestinaltract by any suitable route, including intraventricular, intrathecal,and epidural injection, and enema. Intraventricular injection can befacilitated by an intraventricular catheter, for example, attached to areservoir, such as an Ommaya reservoir.

[0397] Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the Piperazine Compounds can be formulated as asuppository, with traditional binders and excipients such astriglycerides.

[0398] In another embodiment, the Piperazine Compounds can be deliveredin a vesicle, in particular a liposome (see Langer, Science249:1527-1533 (1990) and Treat et al., Liposomes in the Therapyoflnfectious Disease and Cancer 317-327 and 353-365 (1989).

[0399] In yet another embodiment, the Piperazine Compounds can bedelivered in a controlled-release system or sustained-release system(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)). Other controlled- orsustained-release systems discussed in the review by Langer, Science249:1527-1533 (1990) can be used. In one embodiment, a pump can be used(Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed.Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudeket al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease (Langer and Wise eds., 1974); Controlled Drug Bioavailability,Drug Product Design and Performance (Smolen and Ball eds., 1984); Rangerand Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)). In yet anotherembodiment, a controlled- or sustained-release system can be placed inproximity of a target of the Piperazine Compounds, e.g., the spinalcolumn, brain, or gastrointestinal tract, thus requiring only a fractionof the systemic dose.

[0400] The present compositions can optionally comprise a suitableamount of a pharmaceutically acceptable excipient so as to provide theform for proper administration to the animal.

[0401] Such pharmaceutical excipients can be liquids, such as water andoils, including those of petroleum, animal, vegetable, or syntheticorigin, such as peanut oil, soybean oil, mineral oil, sesame oil and thelike. The pharmaceutical excipients can be saline, gum acacia, gelatin,starch paste, talc, keratin, colloidal silica, urea and the like. Inaddition, auxiliary, stabilizing, thickening, lubricating, and coloringagents can be used. In one embodiment, the pharmaceutically acceptableexcipients are sterile when administered to an animal. Water, and in oneembodiment physiological saline, is a particularly useful excipient whenthe Piperazine Compound is administered intravenously. Saline solutionsand aqueous dextrose and glycerol solutions can also be employed asliquid excipients, particularly for injectable solutions. Suitablepharmaceutical excipients also include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The presentcompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents.

[0402] The present compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In one embodiment, the composition is in the formof a capsule (see e.g., U.S. Pat. No. 5,698,155). Other examples ofsuitable pharmaceutical excipients are described in Remington'sPharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed.1995), incorporated herein by reference.

[0403] In one embodiment, the Piperazine Compounds are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. Compositions for oral delivery can be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions can contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

[0404] In another embodiment, the Piperazine Compounds can be formulatedfor intravenous administration. Typically, compositions for intravenousadministration comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lidocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherethe Piperazine Compounds are to be administered by infusion, they can bedispensed, for example, with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the Piperazine Compounds areadministered by injection, an ampule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

[0405] The Piperazine Compounds can be administered bycontrolled-release or sustained-release means or by delivery devicesthat are well known to those of ordinary skill in the art. Examplesinclude, but are not limited to, those described in U.S. Pat. Nos.:3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and5,733,566, each of which is incorporated herein by reference. Suchdosage forms can be used to provide controlled- or sustained-release ofone or more active ingredients using, for example, hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, liposomes, microspheres,or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled- or sustained-releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeingredients of the invention. The invention thus encompasses single unitdosage forms suitable for oral administration such as, but not limitedto, tablets, capsules, gelcaps, and caplets that are adapted forcontrolled- or sustained-release.

[0406] Controlled- or sustained-release pharmaceutical compositions canhave a common goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained counterparts. In one embodiment, acontrolled- or sustained-release composition comprises a minimal amountof a Piperazine Compound to cure or control the condition in a minimumamount of time. Advantages of controlled- or sustained-releasecompositions include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition, controlled- orsustained-release compositions can favorably affect the time of onset ofaction or other characteristics, such as blood levels of the PiperazineCompound, and can thus reduce the occurrence of adverse side effects.

[0407] Controlled- or sustained-release compositions can initiallyrelease an amount of a Piperazine Compound that promptly produces thedesired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the Piperazine Compound to maintainthis level of therapeutic or prophylactic effect over an extended periodof time. To maintain a constant level of the Piperazine Compound in thebody, the Piperazine Compound can be released from the dosage form at arate that will replace the amount of Piperazine Compound beingmetabolized and excreted from the body. Controlled- or sustained-releaseof an active ingredient can be stimulated by various conditions,including but not limited to, changes in pH, changes in temperature,concentration or availability of enzymes, concentration or availabilityof water, or other physiological conditions or compounds.

[0408] The amount of the Piperazine Compound that is effective in thetreatment or prevention of a Condition can be determined by standardclinical techniques. In addition, in vitro or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the Condition and should bedecided according to the judgment of the practitioner and each patient'scircumstances in view of published clinical studies. Suitable effectivedosage amounts, however, range from about 10 micrograms to about 2500milligrams about every 4 h, although they are typically about 100 mg orless. In one embodiment, the effective dosage amount ranges from about0.01 milligrams to about 100 milligrams of a Piperazine Compound aboutevery 4 h, in another embodiment, about 0.020 milligrams to about 50milligrams about every 4 h, and in another embodiment, about 0.025milligrams to about 20 milligrams about every 4 h. The effective dosageamounts described herein refer to total amounts administered; that is,if more than one Piperazine Compound is administered, the effectivedosage amounts correspond to the total amount administered.

[0409] Where a cell capable of expressing mGluR5 or mGluR1 is contactedwith a Piperazine Compound in vitro, the amount effective for inhibitingthe receptor function in a cell will typically range from about 0.01μg/L to about 5 mg/L, in one embodiment, from about 0.01 μg/L to about2.5 mg/L, in another embodiment, from about 0.01 μg/L to about 0.5 mg/L,and in another embodiment, from about 0.01 μg/L to about 0.25 mg/L of asolution or suspension of a pharmaceutically acceptable carrier orexcipient. In one embodiment, the volume of solution or suspension isfrom about 1 μL to about 1 mL. In another embodiment, the volume ofsolution or suspension is about 200 μL.

[0410] Where a cell capable of expressing mGluR5 or mGluR1 is contactedwith a Piperazine Compound in vivo, the amount effective for inhibitingthe receptor function in a cell will typically range from about 0.01 mgto about 100 mg/kg of body weight per day, in one embodiment, from about0.1 mg to about 50 mg/kg body weight per day, and in another embodiment,from about 1 mg to about 20 mg/kg of body weight per day.

[0411] The Piperazine Compounds can be assayed in vitro or in vivo forthe desired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.

[0412] The present methods for treating or preventing a Condition in ananimal in need thereof can further comprise administering to the animalbeing administered a Piperazine Compound another therapeutic agent. Inone embodiment, the other therapeutic agent is administered in aneffective amount.

[0413] The present methods for inhibiting mGluR5 function in a cellcapable of expressing mGluR5 can further comprise contacting the cellwith an effective amount of another therapeutic agent.

[0414] The present methods for inhibiting mGluR1 function in a cellcapable of expressing mGluR1 can further comprise contacting the cellwith an effective amount of another therapeutic agent.

[0415] The other therapeutic agent includes, but is not limited to, anopioid agonist, a non-opioid analgesic, a non-steroidalanti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, anantiemetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca2+-channel blocker, an anticancer agent, an agentfor treating or preventing one or more Conditions, and mixtures thereof.

[0416] Effective amounts of the other therapeutic agents are well knownto those skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective-amount range. In one embodiment of the invention, whereanother therapeutic agent is administered to an animal, the effectiveamount of the Piperazine Compound is less than its effective amountwould be where the other therapeutic agent is not administered. In thiscase, without being bound by theory, it is believed that the PiperazineCompounds and the other therapeutic agent act synergistically to treator prevent a Condition.

[0417] Examples of useful opioid agonists include, but are not limitedto, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

[0418] In certain embodiments, the opioid agonist is selected fromcodeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine,dihydromorphine, morphine, tramadol, oxymorphone, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

[0419] Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, non-steroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

[0420] Examples of useful Cox-II inhibitors and 5-lipoxygenaseinhibitors, as well as combinations thereof, are described in U.S. Pat.No. 6,136,839, which is hereby incorporated by reference in itsentirety. Examples of useful Cox-II inhibitors include, but are notlimited to, rofecoxib and celecoxib.

[0421] Examples of useful antimigraine agents include, but are notlimited to, alpiropride, dihydroergotamine, dolasetron, ergocomine,ergocominine, ergocryptine, ergot, ergotamine, flumedroxone acetate,fonazine, lisuride, lomerizine, methysergide oxetorone, pizotyline, andmixtures thereof.

[0422] The other therapeutic agent can also be an agent useful forreducing any potential side effects of a Piperazine Compounds. Forexample, the other therapeutic agent can be an antiemetic agent.Examples of useful antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, odansetron, granisetron, hydroxyzine,acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide,bietanautine, bromopride, buclizine, clebopride, cyclizine,dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride,tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron,and mixtures thereof.

[0423] Examples of useful β-adrenergic blockers include, but are notlimited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol,befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol,bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride,butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol,cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol,levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol,nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol,pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol,talinolol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

[0424] Examples of useful anticonvulsants include, but are not limitedto, acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadionf, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthrryl)hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

[0425] Examples of useful antidepressants include, but are not limitedto, binedaline, caroxazone, citalopram, dimethazan, fencamine,indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimelidine.

[0426] Examples of useful Ca2+-channel blockers include, but are notlimited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil,mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine,aranidipine, barnidipine, benidipine, cilnidipine, efonidipine,elgodipine, felodipine, isradipine, lacidipine, lercanidipine,manidipine, nicardipine, nifedipine, nilvadipine, nimodipine,nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine,lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.

[0427] Examples of useful anticancer agents include, but are not limitedto, acivicin, aclarubicin, acodazole hydrochloride, acronine,adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflomithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alfa-2a, interferonalfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-I a,interferon gamma-I b, iproplatiri, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozotocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

[0428] Examples of other anti-cancer drugs include, but are not limitedto, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflomithine; elemene; emitefuir; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin—N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;odansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxelderivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; rasinhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoictin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

[0429] Examples of useful therapeutic agents for treating or preventingUI include, but are not limited to, propantheline, imiprarnine,hyoscyamine, oxybutynin, and dicyclomine.

[0430] Examples of useful therapeutic agents for treating or preventingan addictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

[0431] Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

[0432] Examples of usefuil therapeutic agents for treating or preventinganxiety include, but are not limited to, benzodiazepines, such asalprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam,halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam,prazepam, quazepam, temazepam, and triazolam; non-benzodiazepine agents,such as buspirone, gepirone, ipsapirone, tiospirone, zolpicone,zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g.,amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital,methohexital, pentobarbital, phenobarbital, secobarbital, andthiopental; and propanediol carbamates, such as meprobamate andtybamate.

[0433] Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

[0434] Examples of useful therapeutic agents for treating or preventinga seizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

[0435] Examples of useful therapeutic agents for treating or preventingstroke include, but are not limited to, anticoagulants such as heparin,agents that break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

[0436] Examples of useful therapeutic agents for treating or preventinga pruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below; menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

[0437] Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

[0438] Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide.

[0439] Examples of useful therapeutic agents for treating or preventingALS include, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

[0440] Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

[0441] Examples of useful therapeutic agents for treating or preventinga migraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

[0442] Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT₃ receptor antagonistssuch as odansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazine, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

[0443] Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

[0444] Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotiline, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlafaxine; selectiveserotonin reuptake inhibitors such as fluoxetine, fluvoxamine,paroxetine, and setraline; monoamine oxidase inhibitors such asisocarboxazid, pargyline, phenelzine, and tranylcypromine; andpsychostimulants such as dextroamphetamine and methylphenidate.

[0445] A Piperazine Compound and the other therapeutic agent can actadditively or, in one embodiment, synergistically. In one embodiment, aPiperazine Compound is administered concurrently with anothertherapeutic agent. In one embodiment, a composition comprising aneffective amount of a Piperazine Compound and an effective amount ofanother therapeutic agent can be administered. Alternatively, acomposition comprising an effective amount of a Piperazine Compound anda different composition comprising an effective amount of anothertherapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a Piperazine Compound is administeredprior or subsequent to administration of an effective amount of anothertherapeutic agent. In this embodiment, the Piperazine Compound isadministered while the other therapeutic agent exerts its therapeuticeffect, or the other therapeutic agent is administered while thePiperazine Compound exerts its preventative or therapeutic effect fortreating or preventing a Condition.

[0446] In another embodiment a composition of the invention is preparedby a method comprising admixing a Piperazine Compound andpharmaceutically acceptable salt and a pharmaceutically acceptablecarrier or excipient. Admixing can be accomplished using methods wellknown for admixing a compound (or salt) and a pharmaceuticallyacceptable carrier or excipient. In one embodiment the PiperazineCompound or the pharmaceutically acceptable salt of the Compound ispresent in the composition in an effective amount.

5.7 Kits

[0447] The invention encompasses kits that can simplify theadministration of a Piperazine Compound to an animal.

[0448] A typical kit of the invention comprises a unit dosage form of aPiperazine Compound. In one embodiment, the unit dosage form is acontainer, which can be sterile, containing an effective amount of aPiperazine Compound and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the Piperazine Compound to treat a Condition. Thekit can also further comprise a unit dosage form of another therapeuticagent, for example, a container containing an effective amount of theother therapeutic agent. In one embodiment, the kit comprises acontainer containing an effective amount of a Piperazine Compound and aneffective amount of another therapeutic agent. Examples of othertherapeutic agents include, but are not limited to, those listed above.

[0449] Kits of the invention can further comprise a device that isuseful for administering the unit dosage forms. Examples of such adevice includes, but are not limited to, a syringe, a drip bag, a patch,an inhaler, and an enema bag.

[0450] The following examples are set forth to assist in understandingthe invention and should not, of course, be construed as specificallylimiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of all equivalents now knownor later developed, which would be within the purview of those skilledin the art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

6. EXAMPLES

[0451] Examples 1-68 relate to the synthesis of illustrative PiperazineCompounds.

6.1 Example 1 Synthesis of Compound AA

[0452]

[0453] A solution of 2-chloro-3-nitropyridine E (4.2 g, 27 mmol)(commercially available from Aldrich Chemical Co., Milwaukee, Wis.),t-butyl 1-piperazinecarboxylate F (5.0 g, 27 mmol), and triethylamine(“TEA”) (10 mL) in CH₂Cl₂ (200 mL) was stirred at room temperature for 4h. The solution was then extracted with water, the organic layerseparated and dried (Na₂SO₄), and the organic solvent removed underreduced pressure to provide compound G. Liquid chromatography - massspectral (“LCMS”) analysis showed 100% conversion to compound G.Compound G was redissolved in CH₂Cl₂ (150 mL) and the resulting solutioncooled to 0° C. Trifluoroacetic acid (“TFA”) (60 mL) was then slowlyadded to the solution and the resulting mixture allowed to stirovernight at room temperature. The solution was then evaporated todryness to afford 1-(3-nitro-pyridin-2-yl)-piperazine, compound H, asyellow powder. Compound H was used in final step C without furtherpurification.

[0454] Phenylpropynoic acid I (1.9 g, 13 mmol) was dissolved in 75 mLanhydrous CH₂Cl₂ and oxalyl chloride (3.8 mL, 43 mmol) was addedfollowed by 2 drops of dimethylformamide. The resulting mixture wasprotected from exposure to moisture with a drying tube and stirred atroom temperature for 2 hours. The solution was then evaporated todryness to afford compound J. Compound J was used in final step Cwithout further purification.

[0455] Compound J, prepared in step B, was dissolved in anhydroustetrahydrofuran (15 mL) and the resulting solution was added dropwise toa solution of compound H (3.0 g) in anhydrous tetrahydrofuran (150 mL)with stirring and the resulting mixture stirred overnight at roomtemperature. The reaction mixture was then washed 3 times with brine,dried (Na₂SO₄), and the solvent removed under reduced pressure toprovide a residue that was purified by chromatography on a silica columnusing 1:1 ethyl acetate/hexane as the eluent to provide compound AA as alight yellow solid (70% yield). The structure of Compound AA wasconfirmed by ¹H NMR and mass spectral (MS) analysis.

[0456] Compound AA: ¹H NMR (CDCl₃) d 8.40 (dd, J=4.4 and 1.6 Hz, 1H),8.21 (dd, J=8.0 and 1.6 Hz, 1H), 7.57 (m, 2H), 7.42 (m, 3H), 6.88 (dd,J=8.0 and 4.4 Hz, 1H), 4.01 (t, J=5.2 Hz, 2H), 3.87 (t, J=5.2 Hz, 2H),3.54 (m, 4H); MS (EI): m/z 359 (M+Na⁺).

6.2 Example 2 Synthesis of Compound AB

[0457]

[0458] To a mixture of compound K (1.2 mmol) (made from the reaction of2-chloro-3-cyanopyridine and t-butyl 1-piperazinecarboxylate, compoundF, according to the method of Step A in Example 1) and PCl₅ (1.2 mmol)in 5 mL of dichloroethane was added, in one portion, 1 mmol (1 eq.) ofcompound I and 2 eq. of diisopropylethylamine (“DIEA”) and the resultingreaction mixture was allowed to stir at 40° C. for 2 h. Thin-layerchromatography demonstrated the complete disappearance of compound K. 5mL of aqueous NaOH (1 N) was added to the reaction mixture and theorganic layer separated. The aqueous layer was then extracted with ethylacetate (3 mL, 2 times) and the organic layers combined, dried(potassium carbonate), and the solvent removed under reduced pressure toprovide a brown oil. The resulting brown oil was dissolved in 1 mL ofdichloromethane (“DCM”) and purified by column chromatography on asilica column (5 g silica). The column was eluted by gradient elutionstarting with 100% hexane and gradually increasing the polarity of thesolvent to 20% ethyl acetate/hexane and then eluting with 5%triethylamine/40% ethyl acetate/55% hexane to provide Compound AB as anoil. High pressure liquid chromatography (“HPLC”) analysis showed thatthe purity of Compound AB was greater than 97%. The structure ofCompound AB was confirmed by ¹H NMR and mass spectral (“MS”) analysis.

[0459] Compound AB: ¹H NMR (CDCl₃) d 3.65 (m, 2H), 3.80 (m, 2H), 3.87(m, 2H), 4.05 (m, 2H), 6.75 (dd, 1H), 7.30-7.50 (m, 2H), 7.60 (m, 2H),7.80 (d, 1H), 8.35 (d, 1H). MS: m/z 317.1 (M+1).

6.3 Example 3 Synthesis of Compounds AE, AX and AY

[0460]

[0461] Compound AX was prepared by reacting1-(6-methyl-3-nitro-pyridin-2-yl)-piperazine with compound I using aprocedure analogous to that used to make Compound AB (Example 6.2). HPLCanalysis showed that the purity of Compound AX was greater than 97%. Thestructure of Compound AX, was confirmed by ¹H NMR and MS analysis.

[0462] Compound AX: ¹H NMR (CDCl₃) d 2.40 (s, 1H), 3.65 (m, 2H), 3.80(m, 2H), 3.87 (m, 2H), 4.05 (m, 2H), 6.60 (d, 1H), 7.30-7.50 (m, 2H),7.60 (m, 2H), 7.65 (d, 1H). MS: m/z 331.2.

[0463] Compounds AE and AY can be prepared by reacting1-(3-chloro-pyridin-2-yl)-piperazine (for Compound AE) or1-(4-methyl-3-nitro-pyridin-2-yl)-piperazine (for Compound AY) withcompound I using a procedure analogous to that used to make Compound AB(Example 6.2).

6.4 Example 4 Synthesis of Compound AO

[0464]

[0465] To a mixture of compound K (1 mmol) (made from the reaction of2-chloro-3-cyanopyridine and t-butyl 1-piperazinecarboxylate, compoundF, according to the method of Step A in Example I) and propargylaldehyde, compound M (1 mmol) in 5 mL of dichloroethane was added, inone portion, 310 mg of sodium triacetoxyborohydride (1.4 mmol, 1.4 eq.)and the resulting reaction mixture was allowed to stir overnight.Thin-layer chromatography demonstrated the complete disappearance ofcompound K. 5 mL of 1 N NaOH was then added to the reaction mixture andthe organic layer separated. The aqueous layer was then extracted withethyl acetate (3 mL, 2 times) and the organic layers combined, dried(potassium carbonate), and the solvent removed under reduced pressure toprovide a brown oil. The resulting brown oil was dissolved in 1 mL ofDCM and purified by column chromatography on a silica column (5 gsilica). The column was eluted by gradient elution starting with 100%hexane and gradually increasing the polarity of the solvent to 20% ethylacetate/hexane and then eluting with 5% triethylamine/40% ethylacetate/55% hexane to provide Compound AO as an oil. HPLC analysisshowed that the purity of Compound AO was greater than 97%. Thestructure of Compound AO was confirmed by ¹H NMR and MS analysis.

[0466] Compound AO: ¹H NMR (CDCl₃) d 2.80-2.90 (m, 4H), 3.60 (m, 2H),3.80-3.90 (m, 4H), 6.75 (dd, 1H), 7.30-7.60 (m, 5H), 7.80 (d, 1H), 8.35(d, 1H). MS: m/z 303.1 (M+1).

6.5 Example 5 Synthesis of Compounds AQ, AW, AZ, BA and BB

[0467]

[0468] Compounds AQ, AW and BB were prepared by reacting compound M with1-(3-chloro-pyridin-2-yl)-piperazine (for Compound AQ),1-(4-methyl-3-nitro-pyridin-2-yl)-piperazine (for Compound AW), or1-(6-methyl-3-cyano-pyridin-2-yl)-piperazine (for Compound BB) using aprocedure analogous to that used to make Compound AO (Example 4). Thestructure of Compounds AQ, AW and BB were confirmed by ¹H NMR and MSanalysis.

[0469] Compound AQ: ¹H NMR (CDCl₃) d 2.75-2.85 (m, 4H), 3.40-3.50 (bs,4H), 3.60 (s, 2H), 6.80 (dd, 1H), 7.30-7.60 (m, 5H), 7.60 (d, 1H), 8.20(d, 1H). MS: m/z 312.1.

[0470] Compound AW: ¹H NMR (CDCl₃) d 2.30 (s, 3H), 2.70-2.80 (m, 4H),3.40-3.60 (m, 4H), 3.65 (s, 2H), 6.65 (d, 1H), 7.30-7.60 (m, 5H), 8.15(d, 1H). MS: m/z 337.2.

[0471] Compound BB: ¹H NMR (CDCl₃) d 2.40 (s, 3H), 2.75-2.85 (m, 4H),3.60 (s, 2H), 3.80-3.90 (m, 4H), 6.60 (d, 1H), 7.30-7.50 (m, 5H), 7.65(d, 1H). MS: m/z 317.1.

[0472] Compounds AZ and BA can be prepared by reacting4-phenyl-3-butyn-2-one and 1-(3-nitro-pyridin-2-yl)-piperazine (forCompound AZ) or 1-(3-cyano-pyridin-2-yl)-piperazine (for Compound BA)using a procedure analogous to that used to make Compound AO (Example 4)as depicted below.

6.6 Example 6 Synthesis of Compounds BC and BD

[0473]

[0474] Compounds BC and BD were prepared by reacting compound H(prepared according to the method described in Step A of Example 1) withthe appropriately substituted phenylacetylene and paraformaldehyde indioxane at 70° C. in the presence of CuCl. The structure of Compounds BCand BD was confirmed by ¹H NMR.

[0475] Compound BC: ¹H NMR (CDCl₃) d 8.34 (dd, 1H, J=4.5, 1.75), 8.13(dd, 1H, J=8.05, 1.75), 7.46 (dd, 1H, J=7.37, 1.94), 7.38 (dd, 1H,J=7.89, 1.34), 7.27-7.17 (m, 2H), 6.75 (dd, 1H, J=8.04, 4.52), 3.66 (s,2H), 3.55 (t, 1H, J=4.94), 2.79 (t, 1H, J=4.95).

[0476] Compound BD: ¹H NMR (CDCl₃) d 8.35 (dd, 1H, J=4.53, 1.74), 8.15(dd, 1H, J=8.03, 1.73), 7.56 (m, 4H), 6.78 (dd, 1H, J=8.05,4.54), 3.61(s, 2H), 3.56 (t, 1H, J=4.92), 2.77 (t, 1H, J=4.94).

6.7 Example 7 Synthesis of Compound BE

[0477]

[0478] Compound BE was prepared by reacting compound N (preparedaccording to the method described in Step A of Example 1) with compoundI in the presence of HOBT and DIC in methylene chloride at 70° C. Thestructure of Compound BE was confirmed by ¹H NMR.

[0479] Compound BE: ¹H NMR (CDCl₃) δ 8.39 (m, 1H), 8.17 (m, 1H), 7.55(m, 1H), 7.43 (m, 3H), 6.85 (dd, J=4.5, 8.03 Hz, 1H), 4.55 (m, 1H), 4.42(m, 1.5H), 4.26 (dt, J=3.0, 13.3 Hz, 0.5H), 3.66 (dd, J=3.54, 13.3 Hz,0.5 H), 3.52 (m, 1H), 3.40 (m, 1H), 3.25 (dd, J=3.54, 13.3 Hz, 0.5H),3.10 (m, 0.5H), 1.35 (d, J=6.72 Hz, 1.5H), 1.30 (d, J=6.72 Hz, 1.5H).

6.8 Example 8 Synthesis of Compound BF

[0480]

[0481] Compound BF was prepared by reacting compound O (preparedaccording to the method described in Step A of Example 1) with compoundI in the presence of HOBT and DIC in methylene chloride at 70° C. Thestructure of Compound BF was confirmed by ¹H NMR.

[0482] Compound BF: ¹H NMR (CDCl₃) δ 8.39 (d, J=4.3 Hz, 1H), 8.20 (dd,J=1.69, 8.04 Hz, 1H), 7.55 (m, 2H), 7.43 (m, 3H), 6.85 (dd, J=4.5, 8.04Hz, 1H), 4.90 (m, 0.5H), 4.75 (m, 0.5H), 4.42 (dt, J=3.0, 10.5 Hz,0.5H), 4.30 (t, J=3.0, 10.5 Hz, 0.5H), 3.80 (m, 2.5H), 3.45 (m, 1.5H),3.12 (m, 1H), 1.43 (d, J 6.78 Hz, 1.5H), 1.32 (d, J=6.78 Hz, 1.5H).

6.9 Example 9 Synthesis of Compound AP

[0483]

[0484] A mixture of compound H (145 mg, 0.7 mmol) (p)repared accordingto the method described in Step A of Example 1), 4 Å molecular sieves(0.6 g), and phenyipropargyl aldehyde, compound M, (85 μL, 0.7 mmol) in4 mL of anhydrous methanol was stirred at room temperature for 10 min.Sodium triacetoxyborohydride (177 mg, 0.8 mmol) was then added to themixture and the mixture allowed to stir at room temperature for 30 min.5 mL of aqueous NaOH (3 N) was then added to the reaction mixture andthe reaction mixture was extracted with ethyl acetate. The organic layerwas separated, dried, and the solvent removed under reduced pressure toprovide a residue that was purified by column chromatography using asilica gel column to provide Compound AP as a yellow oil (76% yield).The identity of Compound AP was confirmed by ¹H NMR and MS analysis.

[0485] Compound AP: ¹H NMR (CDCl₃) δ 8.35 (dd, J=4.8 and 2.0 Hz, 1H),8.14 (dd, J=8.0 and 2.0 Hz, 1H), 7.45 (m, 2H), 7.32 (m, 3H), 6.76 (dd,J=8.0 and 4.8 Hz, 1H), 3.60 (s, 2H), 3.57 (t, J=4.8 Hz, 4H), 2.77 (t,J=4.8 Hz, 4H). MS (EI): m/z 323 (M+H)⁺.

6.10 Example 10 Synthesis of Compound AV

[0486]

[0487] A solution of compound H (5 g, 24 mmol) in 250 mL of DCM wascooled to 0° C. and HOBT (1.0 g, 8 mmol), propynoic acid (2 g, 28 mmol)and 4-(dimethylamino)pyridine (100 mg) were added 0° C. Then, DIC (4 mL)was added slowly over a 30 minute period. The resulting mixture waswarmed to 25° C. over about a 14 hour period, then cooled to 0° C. Theprecipitate was removed by filtration. The supernatant was washed with30 mL of aqueous NaOH (2 N) followed by washing with 50 mL of brine. Thesolvent was removed under reduced pressure to provide a residue that waspurified by chromatography on a silica column using 3:7 ethylacetate/hexane as the eluent to provide 5 g of compound P as yellowsolid (80% yield).

[0488] A mixture of compound P (1.0 g), 2-lodopyridine (compound Q; 1.0g), TEA (1 mL) and ethyl acetate (20 mL) was degassed and flushed withnitrogen. Pd[(phenyl)₃P]₂Cl₂ (100 mg) and CuI (50 mg) were added. Theresulting mixture was heated to 50° C. and maintained at thattemperature for 5 hours. Then, the solvent was removed under reducedpressure to provide a residue that was purified by chromatography on asilica column using 1:1 ethyl acetate/hexane as the eluent to provide1.1 g of Compound AV as a yellow solid (84% yield).

[0489] Compound AV: ¹H NMR (CDCl₃) 8.67 (dd, 0.5H, J=1.7 and 4.8 Hz),8.65 (dd, 0.5H, J=1.7 and 4.8 Hz), 8.39 (dd, 1H, J=1.7 and 4.6 Hz), 8.19(dd, 1H, J=1.7 and 8.2 Hz), 7.75 (ddd, 1H, J=1.7, 6.0 and 7.7 Hz), 7.64(dd, 0.5H, J=1.1 and 7.8 Hz), 7.62 (dd, 0.5H, J=1.0 and 7.7 Hz), 7.37(dd, 0.5H, J=4.8 and 7.6 Hz), 7.35 (dd, 0.5H, J=4.8 and 7.6 Hz), 6.87(dd, 1H, J=4.8 and 8.2 Hz), 4.02-4.05 (m, 2H), 3.83-3.87 (m, 2H),3.49-3.55 (m, 4H). MS (EI): m/z 360 (M+23).

6.11 Example 11 Synthesis of Compound BG

[0490] Compound BG was prepared according to Example 10, except that3-iodopyridine was used in place of compound Q.

6.12 Example 12 Synthesis of Compound BG

[0491] Compound BG was prepared from compound P according to Example 10,except that 3-bromopyridine was used in place of compound Q.

[0492] Compound BG: ¹H NMR (CDCl₃) 8.40 (dd, 1H, J=1.7 and 4.6 Hz), 8.22(dd, 1H, J=1.7 and 8.2 Hz), 7.65 (dd, 1H, J=1.5 and 7.8 Hz), 7.46 (dd,1H, J=1.5 and 8.1 Hz), 7.39 (ddd, 1H, J=1.5, 5.8 and 7.9 Hz), 7.31 (ddd,1H, J=1.3, 6.1 and 7.6 Hz), 6.87 (dd, 1H, J=4.6 and 7.9 Hz), 4.09-4.13(m, 2H), 3.85-3.89 (m, 2H), 3.51-3.58 (m, 4H). MS (EI): m/z 370 (M+23).

6.13 Example 13 Synthesis of Compound BH

[0493] Compound BH was prepared according to Example 10, except that2-iodopyrazine was used in place of compound Q.

6.14 Example 14 Synthesis of Compound BI

[0494] Compound BI was prepared according to Example 10, except that2-bromo-6-methoxypyridine was used in place of compound Q.

6.15 Example 15 Synthesis of Compound BJ

[0495] Compound BJ was prepared according to Example 10, except that2-bromo-3-methylpyridine was used in place of compound Q.

6.16 Example 16 Synthesis of Compound BK

[0496] Compound BK was prepared according to Example 10, except that2-iodo-6-methylpyridine was used in place of compound Q.

6.17 Example 17 Synthesis of Compound BL

[0497] Compound BL was prepared according to Example 10, except that2-bromo-5-methylpyridine was used in place of compound Q.

6.18 Example 18 Synthesis of Compound BM

[0498] Compound BM was prepared according to Example 10, except that2-bromo-4-methylpyridine was used in place of compound Q.

6.19 Example 19 Synthesis of Compound BN

[0499] Compound BN was prepared according to Example 10, except that4-iodopyridine was used in place of compound Q.

6.20 Example 20 Synthesis of Compound BO

[0500] Compound BO was prepared according to Example 10, except that5-iodo-2-methoxypyridine was used in place of compound Q.

6.21 Example 21 Synthesis of Compound BP

[0501] Compound BP was prepared according to Example 10, except that2-fluoro-5-iodopyrndine was used in place of compound Q.

6.22 Example 22 Synthesis of Compound CK

[0502] Compound CK was prepared from compound P according to Example 10,except that 4-bromoanisole was used in place of compound Q.

[0503] Compound CK: ¹H NMR (CDCl₃) 8.45 (d, 1H), 8.25 (d, 1H), 7.50-7.60(m, 2H), 6.90-6.70 (m, 3H), 4.05 (dd, 2H), 3.70-3.80 (m, 5H), 3.45-3.55(m, 4H). MS (EI): m/z 367 (M+1).

6.23 Example 23 Synthesis of Compound 100

[0504] Compound 100 was prepared according to Example 1, except that2-chloropyridine was used in place of compound E.

[0505] Compound 100: ¹H NMR (CDCl₃) 8.25 (d, 1H), 7.55-7.65 (m, 3H),7.40-7.46 (m, 3H), 6.70-6.80 (m, 2H), 4,10 (dd, 2H), 3.90 (dd, 2H), 3.80(dd, 2H), 3.75 (dd, 2H). MS (EI): m/z 292 (M+1).

6.24 Example 24 Synthesis of Compound BW

[0506] Compound BW was prepared from compound P according to Example 10,except that 3-bromo-4-fluorotoluene was used in place of compound Q.

[0507] Compound BW: ¹H NMR (CDCl₃) 8.40 (dd, 1H, J=1.3 and 4.6 Hz), 8.21(dd, 1H, J=1.7 and 8.1 Hz), 7.38 (dd, 1H, J=1.9 and 6.6 Hz), 7.21-7.24(m, 1H), 7.02 (dd, 1H, J=8.6 and 8.7 Hz), 6.88 (dd, 1H, J=4.6 and 8.1Hz), 4.01-4.04 (m, 2H), 3.85-3.88 (m, 2H), 3.52-3.56 (m, 4H), 2.34 (s,3H). MS (EI): m/z 370 (M+1).

6.25 Example 25 Synthesis of Compound BQ

[0508] Compound BQ was prepared from compound P according to Example 10,except that 4-bromo-1,2—(methylenedioxy)benzene was used in place ofcompound Q.

[0509] Compound BQ: ¹H NMR (CDCl₃) 8.40 (d, 1H), 8.23 (d, 1H), 7.20 (d,1H), 7.00 (s, 1H), 6.80-6.90 (m, 1H), 6.75 (d, 1H), 6.05 (s, 2H), 4.05(dd, 2H), 3.80 (dd, 2H), 3.70-3.80 (m, 4H). MS (EI): m/z 381 (M+1).

6.26 Example 26 Synthesis of Compound BV

[0510] Compound BV was prepared according to Example 7, except thatcompound H was used in place of compound N and 2-hexynoic acid was usedin place of compound I.

[0511] Compound BV: ¹H NMR (CDCl₃) 8.45 (d, 1H), 8.20 (d, 1H), 6.90 (dd,1H), 4.05 (dd, 2H), 3.80 (dd, 2H), 3.70-3.80 (m, 4H), 2.50 (t, 2H),1.75-1.85 (m, 2H), 1.10 (t, 3H). MS (EI): m/z 303 (M+1).

6.27 Example 27 Synthesis of Compound 286

[0512] Compound 286 was prepared according to Example 1, except that2-chloro-6-methoxy-3-nitropyridine was used in place of compound E.

6.28 Example 28 Synthesis of Compound CH

[0513] Compound CH was prepared according to Example 1, except that2-chloro-3-trifluoromethylpyridine was used in place of compound E.

6.29 Example 29 Synthesis of Compound 283

[0514] Compound 283 was prepared according to Example 1, except that2-chloro-6-methyl-3-nitropyridine was used in place of compound E.

6.30 Example 30 Synthesis of Compound 145

[0515] Compound 145 was prepared according to Example 1, except that2-chloro-5-nitropyridine was used in place of compound E.

6.31 Example 31 Synthesis of Compound 103

[0516] Compound 103 was prepared according to Example 1, except that2-chloro-6-methylpyridine was used in place of compound E.

6.32 Example 32 Synthesis of Compound 160

[0517] Compound 160 was prepared according to Example 1, except that2-chloro-4-methylpyridine was used in place of compound E.

6.33 Example 33 Synthesis of Compound 115

[0518] Compound 115 was prepared according to Example 1, except that2-chloro-5-methylpyridine was used in place of compound E.

6.34 Example 34 Synthesis of Compound CZ

[0519] Compound CZ was prepared according to Example 1, except that2,6-dichloro-3-nitropyridine was used in place of compound E.

6.35 Example 35 Synthesis of Compound DA

[0520] Compound DA was prepared according to Example 1, except that2-chloro-3-carbomethoxypyridine was used in place of compound E.

6.36 Example 36 Synthesis of Compound DB

[0521] Compound DB was prepared according to Example 1, except that2-chloro-6-nitropyridine was used in place of compound E.

6.37 Example 37 Synthesis of Compound 163

[0522] Compound 163 was prepared according to Example 1, except that2,4-dimethyl-6-chloropyridine was used in place of compound E.

6.38 Example 38 Synthesis of Compound DE

[0523] Compound DE was prepared according to Example 7, except thatcompound H was used in place of compound N and 2-butynoic acid was usedin place of compound I.

6.39 Example 39 Synthesis of Compound BT

[0524] Compound BT was prepared according to Example 7, except thatcompound H was used in place of compound N and 2-octynoic acid was usedin place of compound I.

6.40 Example 40 Synthesis of Compound BU

[0525] Compound BU was prepared according to Example 7, except thatcompound H was used in place of compound N and 2-heptynoic acid was usedin place of compound I.

6.41 Example 41 Synthesis of Compound BS

[0526] Compound BS was prepared according to Example 7, except thatcompound H was used in place of compound N and 2-nonynoic acid was usedin place of compound I.

6.42 Example 42 Synthesis of Compound BX

[0527] Compound BX was prepared according to Example 10, except that3,5-difluoroiodobenzene was used in place of compound Q.

6.43 Example 43 Synthesis of Compound BY

[0528] Compound BY was prepared according to Example 10, except that2,4-dimethoxyiodobenzene was used in place of compound Q.

6.44 Example 44 Synthesis of Compound DF

[0529] Compound DF was prepared according to Example 10, except that3-fluoroiodobenzene was used in place of compound Q.

6.45 Example 45 Synthesis of Compound DG

[0530] Compound DG was prepared according to Example 10, except that2-fluoroiodobenzene was used in place of compound Q.

6.46 Example 46 Synthesis of Compound BZ

[0531] Compound BZ was prepared according to Example 10, except that2-chloro-5-iodotoluene was used in place of compound Q.

6.47 Example 47 Synthesis of Compound CA

[0532] Compound CA was prepared according to Example 10, except that4-chloro-2-fluoroiodobenzene was used in place of compound Q.

6.48 Example 48 Synthesis of Compound DH

[0533] Compound DH was prepared according to Example 10, except that2-chloroiodobenzene was used in place of compound Q.

6.49 Example 49 Synthesis of Compound DI

[0534] Compound DI was prepared according to Example 10, except that3-trifluoromethoxyiodobenzene was used in place of compound Q.

6.50 Example 50 Synthesis of Compound CB

[0535] Compound CB was prepared according to Example 10, except that5-chloro-2-methoxyiodobenzene was used in place of compound Q.

6.51 Example 51 Synthesis of Compound CC

[0536] Compound CC was prepared according to Example 10, except that2-fluoro-5-iodotoluene was used in place of compound Q.

6.52 Example 52 Synthesis of Compound DJ

[0537] Compound DJ was prepared according to Example LO, except that4-chloroiodobenzene was used in place of compound Q.

6.53 Example 53 Synthesis of Compound DK

[0538] Compound DK was prepared according to Example 10, except that4-fluoroiodobenzene was used in place of compound Q.

6.54 Example 54 Synthesis of Compound CD

[0539] Compound CD was prepared according to Example 10, except that2,5-difluoroiodobenzene was used in place of compound Q.

6.55 Example 55 Synthesis of Compound DL

[0540] Compound DL was prepared according to Example 10, except that3-nitroiodobenzene was used in place of compound Q.

6.56 Example 56 Synthesis of Compound DN

[0541] Compound DN was prepared according to Example 10, except that4-tert-butyliodobenzene was used in place of compound Q.

6.57 Example 57 Synthesis of Compound CE

[0542] Compound CE was prepared according to Example 10, except that3-chloro-2-fluoroiodobenzene was used in place of compound Q.

6.58 Example 58 Synthesis of Compound CI

[0543] Compound CI was prepared from compound P according to Example 10,except that 2-iodoanisole was used in place of compound Q.

6.59 Example 59 Synthesis of Compound CJ

[0544] Compound CJ was prepared from compound P according to Example 10,except that 3-iodoanisole was used in place of compound Q.

6.60 Example 60 Synthesis of Compound CL

[0545] Compound CL was prepared from compound P according to Example 10,except that 2-iodotoluene was used in place of compound Q.

6.61 Example 61 Synthesis of Compound CM

[0546] Compound CM was prepared from compound P according to Example 10,except that 4-iodotoluene was used in place of compound Q.

6.62 Example 62 Synthesis of Compound CP

[0547] Compound CP was prepared from compound P according to Example 10,except that 3-iodotoluene was used in place of compound Q.

6.63 Example 63 Synthesis of Compound DO

[0548] Compound DO was prepared according to Example 10, except that5-iodo-2-methoxypyridine was used in place of compound Q.

6.64 Example 64 Synthesis of Compound DQ

[0549] Compound DQ was prepared according to Example 10, except that2-fluoro-4-iodopyridine was used in place of compound Q.

6.65 Example 65 Synthesis of Compound DR

[0550] Compound DR was prepared according to Example 10, except that4-iodopyridine was used in place of compound Q.

6.66 Example 66 Synthesis of Compound DS

[0551] Compound DS was prepared according to Example 10, except that2-iodopyridine was used in place of compound Q.

6.67 Example 67 Synthesis of Compound DT

[0552] Compound DT was prepared according to Example 10, except that3-iodopyridine was used in place of compound Q.

6.68 Example 68 Synthesis of Compound DU

[0553] Compound DU was prepared according to Example 10, except that2-fluoro-5-iodopyridine was used in place of compound Q.

6.69 Example 69 Binding of an Illustrative Piperazine Compound to mGluR5

[0554] The following assay demonstrates that Compound AA, anillustrative Piperazine Compound, binds to mGluR5.

[0555] Cell cultures: Primary glial cultures were prepared from corticesof Sprague-Dawley 18 days old embryos. The cortices were dissected andthen dissociated by trituration. The resulting cell homogenate wasplated onto poly-D-lysine precoated T175 flasks (BIOCOAT, commerciallyavailable from Becton Dickinson and Company Inc. of Franklin Lakes,N.J.) in Dulbecco's Modified Eagle's Medium (“DMEM,” pH 7.4), bufferedwith 25 mM HEPES, and supplemented with 15% fetal calf serum (“FCS,”commercially available from Hyclone Laboratories Inc. of Omaha, Nebr.),and incubated at 37° C. and 5% CO₂. After 24 hours, FCS supplementationwas reduced to 10%. On day six, oligodendrocytes and microglia wereremoved by strongly lapping the sides of the flasks. One day followingthis purification step, secondary astrocytes cultures were establishedby subplating onto 96 poly-D-lysine precoated T175 flasks (BIOCOAT) at adensity of 65,000 cells/well in DMEM and 10% FCS. After 24 hours, theastrocytes were washed with serum free medium and then cultured in DMEM,without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mLepidermal growth factor (“EGF”), I mM sodium pyruvate, and1×penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5%CO₂. The procedure allows the expression of the mGluR5 receptor byastrocytes, as demonstrated by S. Miller et al., J. Neuroscience15(9):6103-6109 (1995).

[0556] Assay Protocol: After 3-5 days incubation with EGF, theastrocytes were washed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 mMNaH₂PO₄, 2 mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM Glucose at pH 7.4(“Assay Buffer”) and loaded with the dye Fluo-4 (commercially availablefrom Molecular Probes Inc. of Eugene, Oreg.) using 0.1 mL of AssayBuffer containing Fluo-4 (3 mM final). After 90 minutes of dye loading,the cells were then washed twice with 0.2 mL Assay Buffer andresuspended in 0.1 mL of Assay Buffer. The plates containing theastrocytes were then transferred to a Fluorometric Imaging Plate reader(commercially available from Molecular Devices Corporation of Sunnyvale,Calif.) for the assessment of calcium mobilization flux in the presenceof glutamate and in the presence or absence of antagonist. Aftermonitoring fluorescence for 15 seconds to establish a baseline, DMSOsolutions containing various concentrations of the Piperazine Compoundsdiluted in Assay Buffer (0.05 mL of 4×dilutions for competition curves)were added to the cell plate and fluorescence was monitored for 2minutes. 0.05 mL of a 4×glutamate solution (agonist) was then added toeach well to provide a final glutamate concentration in each well of 10mM. Plate fluorescence was then monitored for an additional 60 secondsafter agonist addition. The final DMSO concentration in the assay was1.0%. In each experiment, fluorescence was monitored as a function oftime and the data analyzed using Microsoft Excel and GraphPad Prism.Dose-response curves were fit using a non-linear regression to determineIC₅₀ value. Compound AA (see Example 6.1) showed an IC₅₀ value of8.9±4.8 nM (mean of 3 experiments). FIG. 1 represents a typical doseresponse curve, i.e., a single experiment, for Compound AA. In eachexperiment each data point was determined two times. These results showthat Compound AA, an illustrative Piperazine Compound, binds to themGluR5 receptor.

6.70 Example 70 Binding of a Piperazine Compound to mGluR5

[0557] Alternatively, the following assay can be used to demonstratethat Piperazine Compounds bind to and modulate the activity of mGluR5and, accordingly, are useful for treating or preventing, e.g., pain.

[0558] 40,000 CHO-rat mGluR5 cells/well are plated into 96 well plate(Costar 3409, Black, clear bottom, 96 well, tissue culture treated) foran overnight incubation in Dulbecco's Modified Eagle's Medium (DMEM, pH7.4) and supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500ug/mL Gencticin. CHO-rat mGluR5 cells are washed and treated withOptimem medium and incubated for 1-4 hours prior to loading cells. Cellplates are then washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mMMgCl₂, 700 μM Na H₂PO₄, 2 mM CaCl₂, 5 mM NaHCO₃, 8 mM Hepes, and 10 mMglucose, pH 7.4) and then incubated with 3 μM Fluo 4 (commerciallyavailable from Molecular probes Inc. of Eugene, Oreg.) in 0.1 mL ofloading buffer. After 90 minutes of dye loading, the cells are thenwashed twice with 0.2 mL loading buffer and resuspended in 0.1 mLloading buffer.

[0559] The plates containing the CHO-rat mGluR5 cells are thentransferred to a Fluorometric Imaging Plate Reader (FLIPR) (commerciallyavailable from Molecular Devices Corporation of Sunnyvale, Calif.) forthe assessment of calcium mobilization flux in the presence of glutamateand in the presence or absence of test compounds. After monitoringfluorescence for 15 seconds to establish a baseline, DMSO solutionscontaining various concentrations of the test compound diluted inloading buffer (0.05 mL of 4×dilutions for the competition curves) areadded to the cell plate and fluorescence is monitored for 2 minutes.0.05 mL of 4×glutamate solution (agonist) is then added to each well toprovide a final glutamate concentration in each well of 10 uM. Platefluorescence is then monitored for an additional 60 seconds afteragonist addition. The final DMSO concentration in the assay is 1.0%. Ineach experiment, fluorescence is monitored as a function of time and thedata analyzed using Microsoft Excel and GraphPad Prism. Dose-responsecurves are fit using a non-linear regression to determine the IC50value. In each experiment, each data point is determined two times.

6.71 Example 71 In Vivo Assays for Treatment or Prevention of Pain

[0560] The following assays can be used to demonstrate that PiperazineCompounds are useful for treating or preventing pain.

[0561] Test Animals: Each experiment uses rats weighing between 200-260g at the start of the experiment. The rats are group-housed and havefree access to food and water at all times, except prior to oraladministration of a Piperazine Compound when food is removed for 16hours before dosing. A control group acts as a comparison to ratstreated with a Piperazine Compound. The control group is administeredthe carrier for the Piperazine Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand Piperazine Compound administered to the test group.

[0562] Acute Pain: To assess the actions of the Piperazine Compounds forthe treatment or prevention of acute pain the rat tail flick test can beused. Rats are gently restrained by hand and the tail exposed to afocused beam of radiant heat at a point 5 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 20 seconds are removed from the tail flick unit andassigned a withdrawal latency of 20 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 5 hoursfollowing administration of a Piperazine Compound. Data are expressed astail flick latency(s) and the percentage of the maximal possible effect(% MPE), i.e., 20 seconds, is calculated as follows:${\% \quad {MPE}} = {\frac{\lbrack {( {{post}\quad {administration}\quad {latency}} ) - ( {{pre}\text{-}{administration}\quad {latency}} )} \rbrack}{( {20\quad s\quad {pre}\text{-}{administration}\quad {latency}} )} \times 100}$

[0563] The rat tail flick test is described in F. E. D'Amour et al., “AMethod for Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941). The results show that Piperazine Compounds are usefulfor treating or preventing acute pain.

[0564] Acute pain can also be assessed by measuring the animal'sresponse to noxious mechanical stimuli by determining the paw withdrawalthreshold (PWT), as described below.

[0565] Inflammatory Pain: To assess the actions of the PiperazineCompounds for the treatment or prevention of inflammatory pain theFreund's complete adjuvant (FCA) model of inflammatory pain is used.FCA-induced inflammation of the rat hind paw is associated with thedevelopment of persistent inflammatory mechanical hyperalgesia andprovides reliable prediction of the anti-hyperalgesic action ofclinically useful analgesic drugs (L. Bartho et al., “Involvement ofCapsaicin-sensitive Neurones in Hyperalgesia and Enhanced OpioidAntinociception in Inflammation,” Naunyn-Schmiedeberg's Archives ofPharmacology 342:666-670 (1990)). The left hind paw of each animal isadministered a 50 μL intraplantar injection of 50% FCA. 24 hour postinjection, the animal is assessed for response to noxious mechanicalstimuli by determining the PWT, as described below. Rats are thenadministered a single injection of 1, 3, 10 or 30 mg/Kg of either aPiperazine Compound, 30 mg/Kg indomethacin or carrier. Responses tonoxious mechanical stimuli are then determined 1, 3, 5 and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:${\% \quad {Reversal}} = {\frac{\lbrack {( {{post}\quad {administration}\quad {PWT}} ) - ( {{pre}\text{-}{administration}\quad {PWT}} )} \rbrack}{\lbrack {( {{baseline}\quad {PWT}} ) - ( {{pre}\text{-}{administration}\quad {PWT}} )} \rbrack} \times 100}$

[0566] Neuropathic Pain: To assess the actions of the PiperazineCompounds for the treatment or prevention of neuropathic pain either theSeltzer model or the Chung model can be used.

[0567] In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a 3/8 curved, reversed-cutting mini-needle and tightlyligated so that the dorsal ⅓ to ½ of the nerve thickness is held withinthe ligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1,3and 5 hours after drug administration for the left rear paw of theanimal. Percentage reversal of neuropathic hyperalgesia is defined as:${\% \quad {Reversal}} = {\frac{\lbrack {( {{post}\quad {administration}\quad {PWT}} ) - ( {{pre}\text{-}{administration}\quad {PWT}} )} \rbrack}{\lbrack {( {{baseline}\quad {PWT}} ) - ( {{pre}\text{-}{administration}\quad {PWT}} )} \rbrack} \times 100}$

[0568] In the Chung model, the spinal nerve ligation model ofneuropathic pain is used to produce mechanical hyperalgesia, thermalhyperalgesia and tactile allodynia in rats. Surgery is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anaesthesiaa 3 cm incision is made and the left paraspinal muscles are separatedfrom the spinous process at the L₄—S2 levels. The L₆ transverse processis carefully removed with a pair of small rongeurs to identify visuallythe L₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, immediately prior to and 1, 3 and 5 hours afterbeing administered a Piperazine Compound for the left rear paw of theanimal. The animal can also be assessed for response to noxious thermalstimuli or for tactile allodynia, as described below. The Chung modelfor neuropathic pain is described in S. H. Kim, “An Experimental Modelfor Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation inthe Rat,” Pain 50(3):355-363 (1992).

[0569] Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy) as described inC. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacology Biochemistry and Behavior 31:451-455 (1988).The maximum weight that can be applied to the hind paw is set at 250 gand the end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia

[0570] The plantar test can be used to assess thermal hyperalgesia. Forthis test, hind paw withdrawal latencies to a noxious thermal stimulusare determined using a plantar test apparatus (commercially availablefrom Ugo Basile of Italy) following the technique described by K.Hargreaves et al., “A New and Sensitive Method for Measuring ThermalNociception in Cutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). Themaximum exposure time is set at 32 seconds to avoid tissue damage andany directed paw withdrawal from the heat source is taken as the endpoint. Three latencies are determined at each time point and averaged.Only the affected (ipsilateral) paw is tested.

[0571] Assessment of Tactile Allodvnia: To assess tactile allodynia,rats are placed in clear, plexiglass compartments with a wire mesh floorand allowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

6.72 Example 72 In Vivo Assays for Treatment or Prevention of Anxiety

[0572] The following assays can be used to demonstrate that PiperazineCompounds are useful for treating or preventing anxiety. The elevatedplus maze test or the shock-probe burying test can be used to assess theanxiolytic activity of Piperazine Compounds in rats or mice.

[0573] The EIevated Plus Maze Test: The elevated plus maze consists of aplatform with 4 arms, two open and two closed (50×10×50 cm enclosed withan open roof). Rats (or mice) are placed in the center of the platform,at the crossroad of the 4 arms, facing one of the closed arms. Timespent in the open arms vs the closed arms and number of open arm entriesduring the testing period are recorded. This test is conducted prior todrug administration and again after drug administration. Test resultsare expressed as the mean time spent in open arms and the mean number ofentries into open arms. Known anxiolytic drugs increase both the timespent in open arms and number of open arm entries. The elevated plusmaze test is described in D. Treit, “Animal Models for the Study ofAnti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews9(2):203-222 (1985).

[0574] The Shock-Probe Burying Test: For the shock-probe burying testthe testing apparatus consists of a plexiglass box measuring 40×30×40cm, evenly covered with approximately 5 cm of bedding material (odorabsorbent kitty litter) with a small hole in one end through which ashock probe (6.5 cm long and 0.5 cm in diameter) is inserted. Theplexiglass shock probe is helically wrapped with two copper wiresthrough which an electric current is administered. The current is set at2 mA. Rats are habituated to the testing apparatus for 30 min on 4consecutive days without the shock probe in the box. On test day, ratsare placed in one corner of the test chamber following drugadministration. The probe is not electrified until the rat touches itwith its snout or fore paws, at which point the rat receives a brief 2mA shock. The 15 min testing period begins once the rat receives itsfirst shock and the probe remains electrified for the remainder of thetesting period. The shock elicits burying behavior by the rat. Followingthe first shock, the duration of time the rat spends spraying beddingmaterial toward or over the probe with its snout or fore paws (buryingbehavior) is measured as well as the number of contact-induced shocksthe rat receives from the probe. Known anxiolytic drugs reduce theamount of burying behavior. In addition, an index of the rat'sreactivity to each shock is scored on a 4 point scale. The total timespent immobile during the 15 min testing period is used as an index ofgeneral activity. The shock-probe burying test is described in D. Treit,1985, supra. The results show that Piperazine Compounds are useful fortreating or preventing anxiety.

6.73 Example 73 In Vivo Assays for Treatment or Prevention of anAddictive Disorder

[0575] The following assays can be used to demonstrate that PiperazineCompounds are useful for treating or preventing an addictive disorder.The condition place preference test or drug self-administration test canbe used to assess the ability of Piperazine Compounds to attenuate therewarding properties of known drugs of abuse.

[0576] The Condition Place Preference Test: The apparatus for theconditioned place preference test consists of two large compartments(45×45×30 cm) made of wood with a plexiglass front wall. These two largecompartments are distinctly different. Doors at the back of each largecompartment lead to a smaller box (36×18×20 cm) box made of wood,painted grey, with a ceiling of wire mesh. The two large compartmentsdiffer in terms of shading (white vs black), level of illumination (theplexiglass door of the white compartment is covered with aluminum foilexcept for a window of 7×7 cm), texture (the white compartment has a 3cm thick floor board (40×40 cm) with nine equally spaced 5 cm diameterholes and the black has a wire mesh floor), and olfactory cues (salinein the white compartment and 1 mL of 10% acetic acid in the blackcompartment). On habituation and testing days, the doors to the smallbox remain open, giving the rat free access to both large compartments.

[0577] The first session that a rat is placed in the apparatus is ahabituation session and entrances to the smaller grey compartment remainopen giving the rat free access to both large compartments. Duringhabituation, rats generally show no preference for either compartment.Following habituation, rats are given 6 conditioning sessions. Rats aredivided into 4 groups: carrier pre-treatment+carrier (control group),Piperazine Compound pre-treatment+carrier, carrierpre-treatment+morphine, Piperazine Compound pre-treatment+morphine.During each conditioning session the rat is injected with one of thedrug combinations and confined to one compartment for 30 min. On thefollowing day, the rat receives a carrier +carrier treatment and isconfined to the other large compartment. Each rat receives threeconditioning sessions consisting of 3 drug combination-compartment and 3carrier-compartment pairings. The order of injections and thedrug/compartment pairings are counterbalanced within groups. On the testday, rats are injected prior to testing (30 min to 1 hour) with eithermorphine or carrier and the rat is placed in the apparatus, the doors tothe grey compartment remain open and the rat is allowed to explore theentire apparatus for 20 min. The time spent in each compartment isrecorded. Known drugs of abuse increase the time spent in thedrug-paired compartment during the testing session. If the PiperazineCompound blocks the acquisition of morphine conditioned place preference(reward), there will be no difference in time spent in each side in ratspre-treated with a Piperazine Compound and the group will not bedifferent from the group of rats that was given carrier+carrier in bothcompartments. Data will be analyzed as time spent in each compartment(drug combination-paired vs carrier-paired). Generally, the experimentis repeated with a minimum of 3 doses of a Piperazine Compound.

[0578] The Drug Self-Administration Test: The apparatus for the drugself-administration test is a standard commercially available operantconditioning chamber. Before drug trials begin rats are trained to pressa lever for a food reward. After stable lever pressing behavior isacquired, rats are tested for acquisition of lever pressing for drugreward. Rats are implanted with chronically indwelling jugular cathetersfor i.v. administration of compounds and are allowed to recover for 7days before training begins. Experimental sessions are conducted dailyfor 5 days in 3 hour sessions. Rats are trained to self-administer aknown drug of abuse, such as morphine. Rats are then presented with twolevers, an “active” lever and an “inactive” lever. Pressing of theactive lever results in drug infusion on a fixed ratio 1 (FR1) schedule(i.e., one lever press gives an infusion) followed by a 20 second timeout period (signaled by illumination of a light above the levers).Pressing of the inactive lever results in infusion of excipient.Training continues until the total number of morphine infusionsstabilizes to within ±10% per session. Trained rats are then used toevaluate the effect of Piperazine Compounds pre-treatment on drugself-administration. On test day, rats are pre-treated with a PiperazineCompound or excipient and then are allowed to self-administer drug asusual. If the Piperazine Compound blocks the rewarding effects ofmorphine, rats pre-treated with the Piperazine Compound will show alower rate of responding compared to their previous rate of respondingand compared to excipient pre-treated rats. Data is analyzed as thechange in number of drug infusions per testing session (number ofinfusions during test session—number of infusions during trainingsession).

6.74 Example 74 Functional Assay for Characterizing mGluR1 AntagonisticProperties

[0579] The following assay can be used to demonstrate that PiperazineCompounds bind to and modulate the activity of mGluR5 and, accordingly,are useful for treating or preventing, e.g., pain. Functional assays forthe characterization of mGluR1 antagonistic properties are well known inthe art. For example, the following procedure can be used.

[0580] cDNA encoding rat mGluR1 a receptor is obtained from, e.g., Prof.S. Nakanishi (Kyoto, Japan). It is transiently transfected into HEK-EBNAcells using a procedure described by Schlaeger et al., New Dev. NewAppl. Anim. Cell Techn., Proc. ESACT Meet., 15^(th)à (1998), 105-112 and117-120. [Ca²⁺] measurements are performed on mGluR1a transfectedHEK-EBNA cells after incubation of the cells with Fluo-3 AM (0.5 μMfinal concentration) for 1 hour at 37° C. followed by 4 washes withassay buffer (DMEM supplemented with Hank's salt and 20 mM HEPES. [Ca²⁺]measurements are done using a flurometric imaging plate reader, e.g.,FLIPR. 10 μM glutamate as agonist is used to evaluate the potency of theantagonists.

[0581] Increasing concentrations of antagonists are applied to the cells5 minutes prior to application of the agonist. The inhibition(antagonists) curves are fitted with appropriate software, for example,the four-parameter logistic equation giving IC₅₀ and Hill coefficientusing the iterative nonlinear curve fitting software Origin fromMicrocal Software Inc., Northampton, Mass.

[0582] The present invention is not to be limited in scope by thespecific embodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

[0583] A number of references have been cited, the entire disclosures ofwhich are incorporated herein by reference.

What is claimed is:
 1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —C(O)—,—C(S)—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄ alkyl)(C₁-C₄ alkyl)-, —CH(phenyl)-or —C(phenyl)₂-, each phenyl independently being unsubstituted orsubstituted with one or more R₇ groups; each R₁ is independently —H,—(C₁-C₃)alkyl, —O(C₁-C₃ alkyl), -halo, —OCF₃, —NO₂, —OH, —CN, —S(O)₂R₄,—C(O)OR₄, —OC(O)R₄, —NH₂ or —NHR₄; R₂ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₃ groups, orR₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each of which is unsubstitutedor substituted with one or more R₅ groups, or R₂ is -(5- to10-membered)heteroaryl, which is unsubstituted or substituted with oneor more R₅′ groups; each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂,═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄; each R₄ is independently —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃or —CH(halo)₂; each R₅ is independently —(C₁-C₆)alkyl, —O(Cl —C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄; each R₅′ is independently —(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄; each R₆ is independently —(C₁-C₃ alkyl), —CH₂OH,—OH, -halo, —NO₂, —CN or —NH₂; each R₇ is independently —(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, halo, —C(halo)₃ or —OC(halo)₃; m is 0, 1 or 2; and n isan integer from 1-4.
 2. The compound or a pharmaceutically acceptablesalt of the compound of claim 1, wherein A is —C(O)—.
 3. The compound ora pharmaceutically acceptable salt of thecompound of claim 2, wherein: nis 1; R₁ is substituted at the 3-position of the pyridyl ring and is—CH₃, -halo, —NO₂—OH or —CN; and R₂ is -phenyl, -naphthyl or —(C₁₄)aryl,each which is unsubstituted or substituted with one or more R₅ groups.4. The compound or a pharmaceutically acceptable salt of thecompound ofclaim 2, wherein: n is 1; R₁ is substituted at the 3-position of thepyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN; and R₂ is -(5- to10-membered)heteroaryl, which is unsubstituted or substituted with oneor more R₅′ groups.
 5. The compound or a pharmaceutically acceptablesalt of thecompound of claim 2, wherein: n is 1; R₁ is substituted atthe 3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN;and R₂ is —(C₁-C₁₀)alkyl, which is unsubstituted or substituted with oneor more R₃ groups.
 6. The compound or a pharmaceutically acceptable saltof the compound of claim 1, wherein m is 1 and R₆ is attached to acarbon atom adjacent to the nitrogen atom attached to the A group. 7.The compound or a pharmaceutically acceptable salt of the compound ofclaim 6, wherein R₆ is —CH₃.
 8. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —C(O)—,—C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)-, —C(C₁-C₄ alkyl)(C₁-C₄ alkyl)-,—CH(phenyl)- or —C(phenyl)₂—, each phenyl independently beingunsubstituted or substituted with one or more R₇ groups; each R₁ isindependently —H, —(C₁-C₃)alkyl, —O(C₁-C₃ alkyl), -halo, —OCF₃, —NO₂,—OH, —CN, —S(O)₂R₄, —C(O)OR₄, —OC(O)R₄, —NH₂ or —NHR₄; R₂ is—(C₁-C₁₀)alkyl, —(C₂-C1 ₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl or—(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted or substitutedwith one or more R₃ groups, or R₂ is -phenyl, -naphthyl or —(C₁₄)aryl,each of which is unsubstituted or substituted with one or more R₅groups; each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂, ═NR₄,—CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄,—S(O)R₄ or —S(O)₂R₄; each R₄ is independently —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃or —CH(halo)₂; each R₅ is independently —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—OC(halo)₃, —CH(halo)₂, —OCH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄,—SR₄, —S(O)R₄ or —S(O)₂R₄; each R₆ is independently —(C₁-C₃ alkyl),—CH₂OH, —OH, -halo, —NO₂, —CN or —NH₂; each R₇ is independently—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo, —C(halo)₃ or —OC(halo)₃; m is 0, 1or 2; and n is an integer from 1-4.
 9. The compound or apharmaceutically acceptable salt of the compound of claim 8, wherein Ais —C(O)—.
 10. The compound or a pharmaceutically acceptable salt of thecompound of claim 9, wherein: n is 1; R₁ is substituted at the3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN; andR₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each which is unsubstituted orsubstituted with one or more R₅ groups.
 11. The compound or apharmaceutically acceptable salt of the compound of claim 9, wherein: nis 1; R₁ is substituted at the 3-position of the pyridyl ring and is—CH₃, -halo, —NO₂, —OH or —CN; and R₂ is -(5- to 10-membered)heteroaryl,which is unsubstituted or substituted with one or more R₅′ groups. 12.The compound or a pharmaceutically acceptable salt of the compound ofclaim 9, wherein: n is 1; R₁ is substituted at the 3-position of thepyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN; and R₂ is—(C₁-C₁₀)alkyl, which is unsubstituted or substituted with one or moreR₃ groups.
 13. The compound or a pharmaceutically acceptable salt of thecompound of claim 8, wherein m is 1 and R₆ is attached to a carbon atomadjacent to the nitrogen atom attached to the A group.
 14. The compoundor a pharmaceutically acceptable salt of the compound of claim 13,wherein R₆ is —CH₃.
 15. A compound of formula:

or a pharmaceutically acceptable salt thereof.
 16. A compound offormula:

or a pharmaceutically acceptable salt thereof, wherein: A is —C(O)—,—C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄ alkyl)-; each R₁ isindependently —(C₁-C₃)alkyl, -halo, —NO₂, —OH, or —CN; m is 0 or 1; n isan integer from 1-4; R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or R₂ is -phenyl, -naphthyl or—(C₁₄)aryl, each of which is unsubstituted or substituted with one ormore R₅ groups, or R₂ is -(5- to 10-membered)heteroaryl which isunsubstituted or substituted with one or more R₅′ groups; each R₃ isindependently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂, ═NR₄, —CH═NR₄,—NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄, —S(O)R₄ or—S(O)₂R₄; each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂; each R₅ isindependently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3- to5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄; each R₅′ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂, —CH═NR₄,—NR₄OH, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄, —S(O)R₄, or—S(O)₂R₄; and each R₆ is —(C₁-C₃)alkyl.
 17. The compound or apharmaceutically acceptable salt of the compound of claim 16, wherein Ais —C(O)—.
 18. The compound or a pharmaceutically acceptable salt of thecompound of claim 17, wherein: n is 1; R₁ is substituted at the3-position of the pyridyl ring and is —CH₃, -halo, —NO₂, —OH or —CN; andR₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each which is unsubstituted orsubstituted with one or more R₅ groups.
 19. The compound or apharmaceutically acceptable salt of the compound of claim 18, wherein: nis 1; R₁ is substituted at the 3-position of the pyridyl ring and is—NO₂; and R₂ is -phenyl, which is unsubstituted or substituted with oneor more R₅ groups selected from —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂.
 20. The compound ora pharmaceutically acceptable salt of the compound of claim 19, whereinR₂ is unsubstituted phenyl.
 21. The compound or a pharmaceuticallyacceptable salt of the compound of claim 16, wherein: A is —C(O)—; n is1; R₁ is —CH₃; and R₂ is unsubstituted phenyl.
 22. The compound or apharmaceutically acceptable salt of the compound of claim 16, wherein: Ais —C(O)—; n is 1; R₁ is substituted at the 3-position of the pyridylring and is —NO₂, -halo or —CN; and R₂ is unsubstituted phenyl.
 23. Thecompound or a pharmaceutically acceptable salt of the compound of claim16, wherein m is 1 and R₆ is attached to a carbon atom adjacent to thenitrogen atom attached to the A group.
 24. The compound or apharmaceutically acceptable salt of the compound of claim 23, wherein R₆is —CH₃.
 25. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —C(O)—,—C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄ alkyl)-; eachR₁ is independently —(Ci—C₃)alkyl, -halo, —NO₂, —OH or —CN; m is 0 or 1;n is an integer from 1-4; R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenylor —(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted orsubstituted with one or more R₃ groups, or R₂ is -phenyl, -naphthyl or—(C₁₄)aryl, each of which is unsubstituted or substituted with one ormore R₅ groups; each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, ═NR₄, —CH═NR₄, —NR₄₀H, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄; each R₄ is independently —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃or —CH(halo)₂; each R₅ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄, or —S(O)₂R₄; and each R₆ is —(C₁-C₃)alkyl. 26.The compound or a pharmaceutically acceptable salt of the compound ofclaim 25, wherein m is 1 and R₆ is attached to a carbon atom adjacent tothe nitrogen atom attached to the A group.
 27. The compound or apharmaceutically acceptable salt of the compound of claim 26, wherein R₆is —CH₃.
 28. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —C(O)—,—C(S)—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄ alkyl)-; each R₁ isindependently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN; n is an integerfrom 1-4; R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₃ groups, or R₂ is -phenyl, -naphthyl or—(C₁₄)aryl, each of which is unsubstituted or substituted with one ormore R₅ groups, or R₂ is -(5- to 10-membered)heteroaryl which isunsubstituted or substituted with one or more R₅′ groups; each R₃ isindependently —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂, ═NR₄, —CH═NR₄,—NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄, —S(O)R₄ or—S(O)₂R₄; each R₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃ or —CH(halo)₂; each R₅ isindependently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3- to5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃,—NO₂, —N(R₄)₂, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄; and each R₅′ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂, —CH═NR₄,—NR₄OH, —COF₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄.29. The compound or a pharmaceutically acceptable salt of the compoundof claim 28, wherein A is —C(O)—.
 30. The compound or a pharmaceuticallyacceptable salt of the compound of claim 29, wherein: n is 1; R₁ issubstituted at the 3-position of the pyridyl ring and is —CH₃, -halo,—NO₂, —OH or —CN; and R₂ is -phenyl, -naphthyl or —(C₁₄)aryl, each whichis unsubstituted or substituted with one or more R₅ groups.
 31. Thecompound or a pharmaceutically acceptable salt of the compound of claim30, wherein: n is 1; R₁ is substituted at the 3-position of the pyridylring and is —NO₂; and R₂ is -phenyl, which is unsubstituted orsubstituted with one or more R₅ groups selected from —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃or —CH(halo)₂.
 32. The compound or a pharmaceutically acceptable salt ofthe compound of claim 31, wherein R₂ is unsubstituted phenyl.
 33. Thecompound or a pharmaceutically acceptable salt of the compound of claim28, wherein: A is —C(O)—; n is 1; R₁ is —CH₃; and R₂ is unsubstitutedphenyl.
 34. The compound or a pharmaceutically acceptable salt of thecompound of claim 28, wherein: A is —C(O)—; n is 1; R₁ is substituted atthe 3-position of the pyridyl ring and is —NO₂, -halo or —CN; and R₂ isunsubstituted phenyl.
 35. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —C(O)—,—C(S)—, —CH₂—, —CH(C₁-C₄ alkyl)- or —C(C₁-C₄ alkyl)(C₁-C₄ alkyl)-; eachR₁ is independently —(C₁-C₃)alkyl, -halo, —NO₂, —OH or —CN; n is aninteger from 1-4; R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkyrlyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenylor —(C₈-C₁₄)tricycloalkenyl, each of which is unsubstituted orsubstituted with one or more R₃ groups, or R₂ is -phenyl, -naphthyl or—(C₁₄)aryl, each of which is unsubstituted or substituted with one ormore R₅ groups; each R₃ is independently —CN, —OH, -halo, —N₃, —NO₂,—N(R₄)₂, ═NR₄, —CH═NR₄, —NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄,—OC(O)OR₄, —SR₄, —S(O)R₄ or —S(O)₂R₄; each R₄ is independently —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)₃or —CH(halo)₂; and each R₅ is independently —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, —CN, —OH, -halo, —N₃, —NO₂, —N(R₄)₂,—CH═NR₄—NR₄OH, —OR₄, —COR₄, —C(O)OR₄, —OC(O)R₄, —OC(O)OR₄, —SR₄, —S(O)R₄or —S(O)₂R₄.
 36. A composition comprising an effective amount of acompound or a pharmaceutically acceptable salt of the compound of claim1 and a pharmaceutically acceptable carrier or excipient.
 37. Acomposition comprising an effective amount of a compound or apharmaceutically acceptable salt of the compound of claim 8 and apharmaceutically acceptable carrier or excipient.
 38. A compositioncomprising an effective amount of a compound or a pharmaceuticallyacceptable salt of the compound of claim 15 and a pharmaceuticallyacceptable carrier or excipient.
 39. A composition comprising aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim 16 and a pharmaceutically acceptable carrier orexcipient.
 40. A composition comprising an effective amount of acompound or a pharmaceutically acceptable salt of the compound of claim25 and a pharmaceutically acceptable carrier or excipient.
 41. Acomposition comprising an effective amount of a compound or apharmaceutically acceptable salt of the compound of claim 28 and apharmaceutically acceptable carrier or excipient.
 42. A compositioncomprising an effective amount of a compound or a pharmaceuticallyacceptable salt of the compound of claim 35 and a pharmaceuticallyacceptable carrier or excipient.
 43. A method for treating pain in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 1. 44. A method for treating pain in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 8. 45. A method for treating pain in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 15. 46. A method for treating pain in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 16. 47. A method for treating pain in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 25. 48. A method for treating pain in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 28. 49. A method for treating pain in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 35. 50. A method for treating anxiety in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 1. 51. A method for treating anxiety in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 8. 52. A method for treating anxiety in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 15. 53. A method for treating anxiety in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 16. 54. A method for treating anxiety in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 25. 55. A method for treating anxiety in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 28. 56. A method for treating anxiety in an animal,comprising administering to an animal in need thereof an effectiveamount of a compound or a pharmaceutically acceptable salt of thecompound of claim
 35. 57. A method for treating Parkinson's disease inan animal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 1. 58. A method for treating Parkinson's diseasein an animal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 8. 59. A method for treating Parkinson's diseasein an animal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 15. 60. A method for treating Parkinson's diseasein an animal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 16. 61. A method for treating Parkinson's diseasein an animal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 25. 62. A method for treating Parkinson's diseasein an animal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 28. 63. A method for treating Parkinson's diseasein an animal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 35. 64. A method for treating depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 1. 65. A method for treating depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 8. 66. A method for treating depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 15. 67. A method for treating depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 16. 68. A method for treating depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 25. 69. A method for treating depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 28. 70. A method for treating depression in ananimal, comprising administering to an animal in need thereof aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 35. 71. A method for inhibiting mGluR5-receptorfunction in a cell, comprising contacting a cell capable of expressingmGluR5 with an effective amount of a compound or a pharmaceuticallyacceptable salt of the compound of claim
 1. 72. A method for inhibitingmGluR5-receptor function in a cell, comprising contacting a cell capableof expressing mGluR5 with an effective amount of a compound or apharmaceutically acceptable salt of the compound of claim
 8. 73. Amethod for inhibiting mGluR5-receptor function in a cell, comprisingcontacting a cell capable of expressing mGluR5 with an effective amountof a compound or a pharmaceutically acceptable salt of the compound ofclaim
 15. 74. A method for inhibiting mGluR5-receptor function in acell, comprising contacting a cell capable of expressing mGluR5 with aneffective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim
 16. 75. A method for inhibiting mGluR5-receptorfunction in a cell, comprising contacting a cell capable of expressingmGluR5 with an effective amount of a compound or a pharmaceuticallyacceptable salt of the compound of claim
 25. 76. A method for inhibitingmGluR5-receptor function in a cell, comprising contacting a cell capableof expressing mGluR5 with an effective amount of a compound or apharmaceutically acceptable salt of the compound of claim
 28. 77. Amethod for inhibiting mGluR5-receptor function in a cell, comprisingcontacting a cell capable of expressing mGluR5 with an effective amountof a compound or a pharmaceutically acceptable salt of the compound ofclaim
 35. 78. A method for preparing a composition, the methodcomprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 1 and a pharmaceutically acceptable carrier orexcipient.
 79. A method for preparing a composition, the methodcomprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 8 and a pharmaceutically acceptable carrier orexcipient.
 80. A method for preparing a composition, the methodcomprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 15 and a pharmaceutically acceptable carrier orexcipient.
 81. A method for preparing a composition, the methodcomprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 16 and a pharmaceutically acceptable carrier orexcipient.
 82. A method for preparing a composition, the methodcomprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 25 and a pharmaceutically acceptable carrier orexcipient.
 83. A method for preparing a composition, the methodcomprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 28 and a pharmaceutically acceptable carrier orexcipient.
 84. A method for preparing a composition, the methodcomprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 35 and a pharmaceutically acceptable carrier orexcipient.